Colorectal cancer (CRC) is the third most common cancer worldwide and despite the abundance of molecular pathways and markers continually being reported, the mortality rates remain high. Hypoxia inducible factor 1alpha (HIF-1α) plays a major role in the response of tumors to hypoxia, and contributes to tumor aggressiveness, invasiveness and resistance to radiotherapy and chemotherapy. Targeting HIF-1α is an attractive strategy, with the potential for disrupting multiple pathways crucial for tumor growth. In the current study, HIF-1α immunohistochemical expression in CRC is reviewed along with the relation to clinical outcome and prognosis. In addition, the significant correlation of HIF-1α to vascular endothelial growth factor (VEGF) expression is reported, as well as the possible role of HIF-1α in predicting the therapeutic response to anti-EGFR therapies. Herein, an overview of the HIF-1α expression in CRC is presented. This review delineates the crucial role that HIF-1α plays in carcinogenesis, tumor angiogenesis and cancer progression. The evaluation of HIF-1α in patient biopsies could be useful as a prognostic and/or predictive biomarker in personalized cancer treatment.