Following surgical removal of one kidney, the other enlarges and increases its function. The mechanism for the sensing of this change and the growth is incompletely understood but begins within days and compensatory renal hypertrophy (CRH) is the dominant contributor to the growth. In many individuals undergoing nephrectomy for cancer or kidney donation this produces a substantial and helpful increase in renal function. Two main mechanisms have been proposed, one in which increased activity by the remaining kidney leads to hypertrophy, the second in which there is release of a kidney specific factor in response to a unilateral nephrectomy that initiates CRH. Whilst multiple growth factors and pathways such as the mTORC pathway have been implicated in experimental studies, their roles and the precise mechanism of CRH are not defined. Unrestrained hypoxia inducible factor activation in renal cancer promotes growth and may play an important role in driving CRH. SUMMARY AT A GLANCE The precise response and process of physiologic compensatory renal hypertrophy (CRH) in the contralateral kidney following nephrectomy remains undefined. This review discusses the clinical determinants, implications and underlying potential mechanisms of CRH. The development of drugs targeting the involved pathways in CRH is suggested to enhance renal function in the diseased remaining kidney.