Hypoxia inducible factor (HIF)-1 alpha and signal transducer and activator of transcription 3 (STAT-3) promote angiogenesis through transcriptional control of angiogenic cytokines such as vascular endothelial growth factor (VEGF). HIF-1 alpha and STAT-3 represent clients of heat shock protein 90 (HSP90). We hypothesize that HSP90 inhibition can impair STAT-3 and HIF-1 alpha activation, resulting in reduced VEGF expression in colorectal cancer (CRC). Protein levels and mRNA levels were measured using western blot and QRT-PCR, respectively, in CRC cell lines. Stable transfection and knockdown of HIF-1 alpha, HSP90 and STAT-3 was performed in the two cell lines. Biologic effects following transfection were confirmed by chemical stimulation of STAT-3 with interleukin 6 (IL6) and HIF-1 alpha with hypoxia, respectively. HSP90 inhibition blocks the activation of its clients, HIF-1 alpha and STAT3, and inhibits VEGF transcription. HIF-1 alpha is located downstream of HSP90 and the two molecules are codependent. Finally, STAT-3 inhibition affects VEGF expression only, thus disrupting angiogenesis. Inhibiting HSP90 is an effective approach to indirectly limit activity via HIF-1 alpha/STAT-3 and subsequent angiogenesis in CRC.