Copper promotion of angiogenesis has been known for more than two decades, but the mechanism of action of copper has not been explored until recently. Copper stimulation of factors involved in vessel formation and maturation, such as vascular endothelial growth factor (VEGF), is mainly responsible for its angiogenesis effect. Copper is required for the activation of hypoxia-inducible factor-1 (HIF-1), a major transcription factor regulating the expression of VEGF. Copper would be transported into nucleus by a copper chaperon for superoxide dismutase-1. Copper is required for HIF-1 interaction with the hypoxia-responsive element of the target genes and ensures the formation of HIF-1 transcriptional complex, thus activating the expression of target genes including VEGF. On the other hand, excess copper can stabilize HIF-1alpha, the rate-limiting component of HIF-1, leading to its accumulation in cytoplasm and thus HIF-1 activation. The essential role of copper in production of VEGF makes it implicated in anti-angiogenesis therapy, such as the application of copper chelators in cancer therapy. However, suppression of angiogenesis is involved in the progression of heart hypertrophy and its transition to heart failure, therefore copper supplementation improves hypertrophic heart disease conditions. This dilemma of copper implications in cancer therapy and heart hypertrophy dictates a comprehensive understanding of a patient's condition before an implementation of copper manipulation therapy for different diseases. In this context, a development of diagnosis for copper metabolic changes as well as a tissue-specific copper manipulation would greatly benefit patients with an implication of copper manipulation therapy.