Diabetes and hypertension are the leading causes of chronic kidney disease and their incidence is increasing at an alarming rate. Both are associated with impairments in the autoregulation of renal blood flow (RBF) and greater transmission of fluctuations in arterial pressure to the glomerular capillaries. The ability of the kidney to maintain relatively constant blood flow, glomerular filtration rate (GFR) and glomerular capillary pressure is mediated by the myogenic response of afferent arterioles working in concert with tubuloglomerular feedback that adjusts the tone of the afferent arteriole in response to changes in the delivery of sodium chloride to the macula densa. Despite intensive investigation, the factors initiating the myogenic response and the signaling pathways involved in the myogenic response and tubuloglomerular feedback remain uncertain. This review focuses on current thought regarding the molecular mechanisms underlying myogenic control of renal vascular tone, the interrelationships between the myogenic response and tubuloglomerular feedback, the evidence that alterations in autoregulation of RBF contributes to hypertension and diabetes-induced nephropathy and the identification of vascular therapeutic targets for improved renoprotection in hypertensive and diabetic patients.