Cancer accounts for nearly one-quarter of deaths in the United States, exceeded only by heart diseases. In 2006, there were 559,888 cancer deaths in the US. Finding effective treatments for cancer is a major challenge among researchers. In solid tumor, hypoxia increases the progression of malignancy and metastasis by promoting angiogenesis. The transcription factor HIF-1 is responsible for the regulation of cellular processes, including glycolysis and angiogenesis. Clinical evidence has determined that expression of HIF-1 is strongly associated with poor patient prognosis. Also, activation of HIF-1 contributes to malignant behavior and therapeutic resistance. In view of these observations, there is a need for anti-cancer treatments that addresses hypoxic related tumors. HIF-1 presents a viable target for inhibition of tumor growth with small molecules. Herein, we describe the design and synthesis of small molecules that inhibit the HIF-1 pathway, as well as mechanistic studies involved in the investigation of the mode of action of these compounds.