Hypophosphatasia (HP) is a rare inherited metabolic bone disease characterized by low serum alkaline phosphatase activity (hypophosphatasaemia) for the age and gender. The disease is caused by pathogenic mutations in the gene that encodes the enzyme tissue-nonspecific alkaline phosphatase (TNSALP). TNSALP is expressed in the liver, kidney and bone, and its substrates are inorganic pyrophosphate (PPi), pyridoxal-5’-phosphate (PLP) / vitamin B6 and phosphoethanolamine (PEA). Therefore, besides low alkaline phosphatase major hallmarks of HP are elevated PLP and PEA concentrations. This ubiquitous enzyme plays a crucial role in the process of bone mineralization and it's deficiency causes rickets or osteomalacia in HP patients. Rickets in HP patients is associated with high levels of calcium and phosphorus, resulting in hypercalciuria and nephrocalcinosis, together with low ALP. HP is divided into seven clinical forms according to the age of onset and symptoms. Perinatal lethal, infantile, childhood and adult type are the four main types, and others are perinatal benign type, odontohypophosphatasia and pseudohypophosphatasia. However, there is considerable genetic and phenotypic variability within different subtypes. The most severe perinatal form of HP presents with severe hypomineralisation and deformed limbs, or even with near abscence of bones and skull. Premature death occurs as a result of respiratory insufficiency. Respiratory failure and seizures due to vitamin B6 deficiency are indicative of a poor prognosis. Craniosynostosis, hypercalcaemia and failure to thrive are frequent features in infants. Fractures are common both in infantile and adult forms of the disease, concomitantly occurring with unexplained chronic pain and fatigue. Premature loss of teeth, is also common in HP, and as an isolated feature found in odontohypophosphatasia. A novel enzyme replacement therapy for HP, asfotase alfa, specifically targeting mineralised tissues, has been available since recently. Even though this is a promising treatment, especially for infantile HP, more knowledge is needed regarding long-term effects and potential secondary adverse effects.