The discovery of small RNAs has shed new light on microRNA (mRNA) regulation and a range of biological processes. The recognition that miRNAs-221 and -222 are sensitive regulators in the endothelium may enable the identification of novel biomarkers and therapeutic targets. Given that endothelial dysfunction precedes the development of atherosclerosis and contributes to the development of cardiovascular damage, circulating miRNAs produced by Endothelial Cells (ECs) are putative biomarkers for a wide range of cardiovascular diseases. Furthermore, EC proliferation and migration have a critical role in the formation of new blood vessels (angiogenesis), an important component of physiological processes and tumour growth. Hence, the use of anti-angiogenic miRNAs might constitute a novel therapeutic strategy. Along with endothelial angiogenesis, several other processes involving ECs (such as neointimal lesion formation, vascular inflammation, lipoprotein metabolism and hypertension) are critical factors in atherogenesis and atherosclerosis. The fact that human blood-derived progenitor cells, endothelial progenitor cells, umbilical vein ECs and quiescent ECs express high levels of miR-221/222 suggests an important role for this miRNA cluster in endothelial (patho) physiology. The present article reviews current knowledge on miRNAs-221/222's regulation roles in endothelial function and disease in general and angiogenesis in particular.