AbstractDistorted mechanotransduction represents the molecular hallmark of disease mechanobiology and is displayed with common features during the development of various pathophysiologies. Polycystins constitute a family of mechanosensitive proteins that facilitate pathogenic signal transduction mechanisms. The main representatives of the family are polycystin‐1 (PC1) and polycystin‐2 (PC2), which function as a mechano‐induced membrane receptor and a calcium‐permeable ion channel, respectively. PC1 and PC2 mediate extracellular mechanical stimulation, induce intracellular molecular signaling and evoke corresponding gene transcription. Recent reports reveal that polycystin‐mediated signaling does not occur in polycystic kidney disease only, where it is most prominently studied. It is also present during the development of clinical entities such as endothelial dysfunction and atheromatosis, deregulation of osteoblast differentiation, cancer development, and psoriasis. In this study, we highlight emerging data that support the overall contribution of polycystins to disease mechanobiology and suggest further exploration of this protein family in diseases generated from force‐bearing tissue structures.