Segmental progeroid syndromes are extremely rare, clinically and genetically heterogeneous disorders characterized by signs of premature / accelerated aging affecting multiple tissues or organs. The aim of the here presented studies was to identify novel monogenic causes of selected segmental progeroid syndromes. Using a combination of different genetic analyses, primarily utilizing next-generation sequencing technologies, accompanied in certain cases by in-depth functional characterization, using both cellular and animal models, I have identified biallelic mutations in SPRTN, MDM2 and POLR3A, as genetic causes of Ruijs-Aalfs syndrome (OMIM # 616200), Lessel-Kubisch syndrome (OMIM # 618681) and Wiedemann–Rautenstrauch syndrome (OMIM # 264090), respectively. The impact of these results is two-fold. First, as in case of identification of novel genetic cause for any monogenic disorder, these results enable establishment of the proper diagnosis, assessment of the prognosis, accurate estimation of the risk of similar disorders in the patient’s family members, and in the growing number of cases enable individualized support and prevention program. Secondly, from the translational perspective, especially mutations in SPRTN and MDM2, offer a strong basis for further studies aiming to further elucidate the pathophysiologic basis of carcinogenesis and hence identify novel and/or improved targeting strategies in cancer therapy.