Myocardial infarction (MI) is a major threat to health worldwide, but today's methods for recovering heart function are limited, which is due largely to the deficient proliferative capacity of adult cardiomyocytes in the human body. To successfully overwhelm this deficiency, we propose a promising hypoxic therapy and highlight its unique role in directly eliciting endogenous myocardial regeneration in vivo. In the hypothesis, sufficient oxygen could be a restrictive factor of-myocardial growth, whereas a moderate hypoxia might stimulate cardiomyocyte proliferation and enhance myocardial regeneration, heart weight and cardiac function recovery. The potential involvements of the hypoxia inducible factor-1 (HIF-1) and its downstream oncogenic signalings were hypothesized and evaluated in detail. Notably, the hypoxic treatment may initiate spontaneous proliferation of pre-existing cardiomyocytes in adult human body, which cannot (or hardly) be achieved by current MI-therapeutic approaches such as cardiovascular drugs, cardiac surgeries and aerobic exercise. The hypoxic therapy will lead to lower surgical risks compared with tissue regeneration in vitro and putative cardiac transplantation. With optimized moderately-low oxygen concentration, available therapeutic frequency and cycles, and controllable side effects, the hypoxic therapy will be a non-invasive, non-surgical, low-cost and low-risk approach to promoting myocardial regeneration in vivo and recovering cardiac function for MI patients who have large-area myocardial necrosis, in addition to other current MI-therapeutic methodologies.