Renal hypertrophy is an important contributor to end-stage renal disease, but little is known about its underlying physiological mechanisms, primarily because of complex etiologies, intricate gene-gene and gene-environment interactions. Kidney mass (Km) can be viewed as a proximal predictor of renal hypertrophy and, consequently, identifying the physiological mechanisms determining Km will probably facilitate our understanding of the factors causing renal hypertrophy. Genetic approaches are powerful in detecting etiological steps involved in pathways and cascades leading to Km control. Recent genetic analyses employing inbred rat models have defined 2 broad categories of genes known as quantitative trait loci (QTLs) responsible for Km. The first class controls Km independently of cardiovascular and hemodynamic phenotypes, suggesting that their underlying physiological mechanisms can be renal-specific and dissociated from those regulating cardiovascular traits. The second class of QTLs modulates Km as well as cardiovascular phenotypes, implying that these renal and cardiovascular traits may share physiological mechanisms. It is expected that some of the mechanisms discovered in animal models may be translated into humans. The strategies of gene discovery for KmQTLs consist of identifying gene candidates (e.g. gene profiling and targeted mutation screening) and in vivo functional validation (e.g. fine congenic resolution, transgenesis and gene targeting).