Heme oxygenase-1 (HO1) degrades heme to carbon monoxide (CO), biliverdin, and ferrous iron. Through these products, HO1 mitigates cellular injury by exerting anti-oxidant, anti-apoptotic, and anti-inflammatory effects. Several lines of evidence indicate that angiogenic factors, such as vascular endothelial growth factor A (VEGF) and stromal cell-derived factor 1 (SDF1), mediate their proangiogenic action in endothelial cells and endothelial progenitor cells through induction of HO1, and reciprocally, VEGF and SDF1 are enhanced by HO1 overexpression. Ferrous iron released during the breakdown of free heme by HO1 is an extremely pro-oxidative molecule that can be rapidly removed by ferritin. Of note, this iron sequestering protein also has been shown to exert some proangiogenic effects. Moreover, our recent data indicate that HO1 is an important mediator of differentiation and function of stem cells, including endothelial and myoblasts progenitors. All of this makes HO1 a promising target for novel cardiovascular therapies. The aim of this review is to discuss the existing knowledge and to propose the therapeutic approaches, which have to consider the necessity of tight regulation of HO1 expression.