Autosomal-dominant polycystic kidney disease (ADPKD) is the most prevalent inherited kidney disease, characterized by growth of bilateral renal cysts, hypertension, and multiple extrarenal complications that eventually can lead to renal failure. It is caused by mutations in PKD1 or PKD2 genes encoding the proteins polycystin-1 and polycystin-2, respectively. Over the past few years, studies investigating the role of primary cilia and polycystins, present not only on the surface of renal tubular cells but also on vascular endothelial cells, have advanced our understanding of the pathogenesis of ADPKD and have shown that mechanisms other than cyst formation also contribute to renal functional decline in this disease. Among them, increased oxidative stress, endothelial dysfunction, and hypoxia may play central roles because they occur early in the disease process and precede the onset of hypertension and renal functional decline. Endothelial dysfunction is linked to higher asymmetric dimethylarginine levels and reduced nitric oxide bioavailability, which would cause regional vasoconstriction and impaired renal blood flow. The resulting hypoxia would increase the levels of hypoxia-inducible-transcription factor 1α and other angiogenetic factors, which, in turn, may drive cyst growth. In this review, we summarize the existing evidence for roles of endothelial dysfunction, oxidative stress, and hypoxia in the pathogenesis of ADPKD.