HIFs have long been associated with resistance to therapy, metastasis, and poor survival rates in cancer patients. In parallel, although the tumor-suppressor p53 acts as the first barrier against tumor transformation, its inactivation also appears to be crucial for enabling cancer progression at advanced stages. p53 has been proposed to antagonize HIF, and emerging evidence suggests that the p53 siblings p63 and p73 also participate in this interplay. Crosstalk between HIFs and the p53 family acts as a determinant of cancer progression through regulating angiogenesis, the tumor microenvironment, dormancy, metastasis, and recurrence. We discuss the possible mechanisms underlying this regulation and the controversies in this field in an attempt to provide a unified view of current knowledge.