Objectives The research objective is to present a structured review of Croatian and European legislative framework, scientific criteria and different practices in the pharmaceutical products interchangeability domain. Such review can help to identify relevant criteria, which should be integrated into guideline for assessment interchangeability of pharmaceuticals in Croatia. This review research has intended to systematize relevant criteria that can ensure straight-forward, coherent and clinically relevant evaluation of therapeutic interchangeability within the definition of the term generic drug substitution. Materials and methods Research methods in this paper rely on the research of accessible literature, from published scientific papers, scientific and expert guidelines, to directives, laws and regulations. Web sites of EU as well as non-EU regulatory institutions were used as a source of relevant information on exact practices of generic substitution. The structure of EU legal framework was described as well as consistency of Croatian legal norms in regulating pharmaceuticals market. Main premises of 2001/83/EZ Directive and also Croatian Law on medicines and Ordinance on approval of marketing authorization for medicinal products from the aspect of generic drug substitution were described. The scientific criteria review for assessment interchangeability of pharmaceuticals was divided into three fundamental categories: regulatory, pharmaceutical and clinical criteria. The regulatory criteria depend, first of all, on legal base of the marketing authorization for pharmaceutical product, which largely defines the extent and content of clinical documentation of the drug. The review of regulatory criteria includes the definition of terms generic drug product and reference drug product with retrospection on data exclusivity period of original drugs, the importance of public available information on medicinal products, the issues of naming medicinal products and designation of prescription status. Pharmaceutical criteria on generic drug substitution include all characteristics of drug quality that have influence on its efficacy and safety: API (active pharmaceutical ingredient) characteristics, excipients and drug formulation characteristics, its pharmaceutical form, strenght, routes and ways of administration and physical characteristics of the drug. Pharmaceutical criteria on generic drug substitution also include data on shelf life, conditions for storage, the package size and specifications of container. Clinical criteria relate to the level of proof for the therapeutic equivalence between medicinal products which is presented in clinical documentation. In the context of generic substitution the fundamental postulates of bioequivalence paradigm were described as a surrogate of the therapeutic equivalence evidence. The basic remarks on investigation of bioequivalence design, and interpretation on its results, is presented as a retrospective view. The consequences of individual and population variability on pharmacokinetic properties and therapeutic response were analyzed. The most significant groups of medicines that need special approach during evaluation of possible interchangeability were identified. The terms which define relations between medicinal products such as essential similarity, pharmaceutical and therapeutic equivalence, pharmaceutical and therapeutic alternative, and also terms such as interchangeability, substitution, prescribability were described. Practice has shown that these terms do not always have an identical use in scientific and regulatory domains. In conclusion, this paper engages in practice experience issues in process of prescribing, dispensing and substitution of medicines. Different aspects of good prescribing practice and good dispensing practice of medicinal products and their influence on generic substitution process were analyzed. Concise review of European and non-European experiences and practices of generic substitution in highly developed healthcare systems was described. The conclusions of professional associations and academic institutions on obstacles and limitations of organization and practice in generic drug substitution were presented. Results Within unique legislative, scientific and economic area variability in therapeutic equivalence evaluations for possible generic substitution can be found. In spite of the approach and methods variability, fundamental criteria for expert assessment do not differ significantly. National regulatory agencies were identified as relevant for competent, coherent and unbiased evaluation of interchangeability of medicines. Healthcare authorities should take part in defining approach and methods for organization of generic substitution providing they have got an insight (and responsibility) for the specific circumstances in the healthcare system organization and efficiency of their key factors. Key factors of the generic substitution process – regulatory institution, physician, pharmacist and patient – and their complementary role in this process were identified. Medications, populations and pathological conditions with limited value of bridging therapeutic equivalence by proof of bioequivalence were identified and they should be integrated into criteria for evaluation of interchangeability. VIII Conclusion Generic substitution is motivated, first of all, with pharmacoeconomic factors, but evaluation of possibility to interchange two medicinal products must be founded on their efficacy and safety evaluation. In spite of variability in approach and methods, cardinal principles in assessment of interchangeability in developed healthcare systems do not differ significantly. Hypothesis: by synthesis existing scientific criteria relevant evaluation of interchangeability of two or more medicinal products that have marketing authorization is possible based on already established data on their quality, efficacy and safety, must be rejected for not being applicable in every specific case. However, the experience shows that in many cases it is possible relevantly to establish the possibility of substitution based on existing data. By observing paper hypothesis through the prism of the economic efficacy of the treatment, every situation in which this evaluation is possible makes a significant contribution to quality and efficiency of whole healthcare system.