The interaction of MYC and hypoxia inducible factors (HIFs) under physiological, non-tumorigenic conditions provides insights into normal homeostatic cellular responses to low oxygen levels (hypoxia). Many tumours contain genetic alterations, such as MYC activation, that can collaborate with HIF to confer metabolic advantages to tumour cells, which tend to exist in a hypoxic microenvironment. This Perspective emphasizes the differences between the transcriptional network that operates under normal homeostatic conditions and the network in a tumorigenic milieu.