Intratumoral heterogeneity is an important factor contributing to metastasis and therapy resistance. The phenotypic diversity of cancer cells within the tumor microenvironment is strongly influenced by microenvironmental factors such as hypoxia. Clinically, hypoxia and the hypoxia inducible transcription factors HIF-1 and HIF-2 are associated with cancer stem cells, metastasis and drug resistance in multiple tumor types. Experimental models have demonstrated an important functional role for HIF signaling in driving CSC, metastatic and drug resistant phenotypes in vitro and in vivo. Here we will review recent studies that highlight novel mechanisms by which hypoxia promotes cancer stem cell, metastatic and drug resistant phenotypes.