Two strains of selectively inbred rats were demonstrated previously to have opposite genetic predisposition to develop hypertension from NaCl ingestion (1, 2), DOCA-NaCl (3), and unilateral renal artery compression without NaCl (3). Using these same strains, similar disparate responses were elicited with two other models for inducing experimental hypertension, namely cortisone and adrenal regeneration. On the basis of these experiences, it is proposed that the genetic substrate will be found to modify significantly the influence of all non-genetic factors considered to play a primary role in the etiology of experimental hypertension. Furthermore, it is suggested that similar genetic and non-genetic factors interact to produce hypertension in man. An hypothesis has been elaborated that is compatible with the experimental data and there is some clinical evidence to support this hypothesis.