Stroke represents a leading cause of long-term disability worldwide, with few therapeutic options available for improving behavioral recovery. Identification of endogenous neural stem and progenitor cells (NSPCs) that are capable of promoting reparative responses following brain injury and stroke make these cells attractive therapeutic targets for stimulating cell replacement and neuronal plasticity. Interest in the mechanisms that support NSPC survival and replenishment of damaged cells within the ischemic brain has led to elucidation of new roles for hypoxia-inducible factor-1α (HIF-1α) in NSPC function. HIF-1α is a well-studied mediator of adaptive cellular responses to hypoxia through direct transcriptional regulation of cellular metabolism and angiogenesis. Recent evidence also indicates novel roles for HIF-1α in stem cell differentiation through modulation of Notch and Wnt/β-catenin signaling pathways. In this review, we will explore the hypothesis that HIF-1α represents an important mediator of NSPC function under both non-pathological conditions and stroke; and plays a central role in the regulation of NSPC response to hypoxia, metabolism and maintenance of the vascular environment of the neural stem cell niche.