Hypoxia-inducible factor (HIF) is a heterodimer that is formed from the association of HIF-α and HIF-1β subunits. HIF acts as a potent inducer of genes involved in angiogenesis and neovascularisation. Three different variants of HIF have been identified to date; HIF-1 and HIF-2 are thought to play key roles in tumour blood vessel formation while with HIF-3 is thought to act as a negative regulator of the hypoxic response. In this study a genetic selection methodology is employed that combines a bacterial reverse two-hybrid system with SICLOPPS (split-intein circular ligation of peptides and proteins), a protocol for the construction of libraries of around a hundred million cyclic peptides using split-inteins in vivo. After construction of the appropriate reverse twohybrid systems, several SICLOPPS libraries were screened for inhibitors of HIF-1 and HIF-2 heterodimerisation. After a number of rounds of secondary screening, the activity of the remaining compounds was ranked by using the HIF reverse two-hybrid systems. The most potent compounds were synthesised as Tat-tagged derivatives for further characterisation in a luciferase based mammalian cell assay. The most potent cyclic peptide exhibited IC50s ranging from 26 to 106 μM in U2OS and MCF7 cell lines.