Chronic kidney disease is characterized by the progressive loss of functional nephrons. This loss means that the remaining nephrons are put under stress and are forced to adapt in order to maintain kidney function. Over the time, the strains imposed by these adaptations result in a vicious circle in which the loss of damaged nephrons results in the damage of the so far healthy nephrons. Hence, the rate of chronic kidney disease progression depends on the ability of the remaining nephrons to cope with stress. This article reviews the molecular pathways involved in the compensation and deterioration process after nephron reduction. In particular, we examine the role of mammalian target of rapamycin complex (mTORC)/serine-threonine protein kinase AKT, epidermal growth factor receptor (EGFR) and unfolded protein response pathways, as well as the pleiotropic function of Lipocalin 2. We also discuss the dual role played by some of these pathways in acute and chronic kidney disease. Finally, the relevance of these experimental finding to human chronic kidney disease is discussed.