Hedgehog (HH) signaling, a critical developmental pathway, has been implicated in cancer initiation and progression. With vismodegib and sonidegib having been approved for clinical use, increasing numbers of HH inhibitors alone and in combination with chemotherapies are in clinical trials. Here we highlight the clinical research on HH antagonists and the genetics of response to these compounds in human cancers. Selectivity of HH inhibitors, determined by decreased pathway transcriptional activity, has been demonstrated in many clinical trials. Patients with advanced/metastatic basal cell carcinoma have benefited the most, whereas HH antagonists did little to improve survival rates in other cancers. Correlation between clinical response and HH gene expression vary among different cancer types. Predicting response and resistance to HH inhibitors presents a challenge and continues to remain an important area of research. New approaches combine standard of care chemotherapies and molecularly targeted therapies to increase the clinical utility of HH inhibitors.