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BACKGROUND MicroRNA-126, a microRNA implicated in blood vessel integrity and angiogenesis is significantly up/down regulated in different physiological and pathological conditions related to angiogenesis such as cardiovascular formation and angiogenesis dependent diseases like Cancer, diabetic microvascular complication, cardiovascular disease, atherosclerosis and stroke. MicroRNA-126 plays a critical role in angiogenesis via regulating the proliferation, differentiation, migration, and apoptosis of angiogenesis related cells such as endothelial cells, vascular smooth muscle cells and pericytes. OBJECTIVE The aim of this review is to investigate the molecular mechanisms and effects of microRNA-126 in angiogenesis process in pathophysiological conditions. METHODS To conduct this review, related articles published between 2001 and 2019 were collected from the PubMed, Web of Science, Google Scholar, Scopus and Scientific Information Database using search terms such as microRNA-126, angiogenesis, cardiovascular disorders, hypoxia, VEFG-A, endothelial cells, VEGF pathway, gene silencing. Then, the qualified articles were reviewed. RESULTS MicroRNA-126 regulates the response of endothelial cells to VEGF, through directly repressing multiple targets, including Sprouty-related EVH1 domain-containing protein 1 (SPRED1) and phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2/p85-b). MicroRNA-126 -3p and microRNA-126 -5p have cell-type and strand-specific functions and also various targets in angiogenesis that lead to regulate angiogenesis via different pathways and consequently diverse response. CONCLUSION MicroRNA-126 can bind to multiple targets and potentially be both positive and negative regulators of gene expression. Thus, microRNA-126 could cause the opposite biological effects depending on the context. As a result, understanding the different cellular pathways that microRNA-126 regulate angiogenesis through them in various situations is a critical aspect in the development of novel and effective treatments for diseases with insufficient angiogenesis. So it is critical to understand its role in governing angiogenesis during pathological and even physiological conditions.