Low oxygen (O2) levels are a naturally occurring feature of embryonic development, adult physiology, and diseases such as those of the cardiovascular system. Although many responses to O2 deprivation are mediated by hypoxia-inducible factors (HIFs), researchers are finding a growing number of HIF-independent pathways that promote O2 conformance and hypoxia tolerance. Here, we describe HIF-independent responses and how they impact cardiovascular tissue homeostasis.