Hypoxia inducible factor (HIF)-1 and HIF-2 are heterodimeric transcription factors mediating the cellular response to hypoxia. Recent data indicate that not only ubiquitous HIF-1${alpha}$, but also more cell-specific HIF-2${alpha}$, is an important regulator of the hypoxia response. Although both ${alpha}$ subunits are highly conservative at protein level, share similar domain structure, heterodimerize with HIF-1${eta}$, and bind to the same DNA sequence called hypoxia responsive element (HRE), their effect on the expression of some genes may vary. In this review we stressed the differences between the isoforms, their structure and expression pattern. Moreover, we described diversity of coactivators and proteins which interact with HIFs, and which are responsible for the specificity of their action. Finally, recent data showing link between HIFs and specific microRNA have been presented.