The hedgehog pathway, for which sonic hedgehog (Shh) is the most prominent ligand, is highly conserved and is tightly associated with embryonic development in a number of species. This pathway is also tightly associated with the development of several types of cancer, including basal cell carcinoma (BCC) and acute promyelocytic leukemia, among many others. Inactivating mutations in Patched-1 (PTCH1), leading to ligand-independent pathway activation, are frequent in several cancer types, but most prominent in BCC. This has led to the development of several compounds targeting this pathway as a cancer therapeutic. These compounds target the inducers of this pathway in Smoothened (SMO) and the GLI transcription factors, although targeting SMO has had the most success. Despite the many attempts at targeting this pathway, only three US FDA-approved drugs for cancers affect the Shh pathway. Two of these compounds, vismodegib and sonidegib, target SMO to suppress signaling from either PTCH1 or SMO mutations that lead to upregulation of the pathway. The other approved compound is arsenic trioxide, which can suppress this pathway at the level of the GLI proteins, although current evidence suggests it also has other targets. This review focuses on the safety and tolerability of these clinically approved drugs targeting the Shh pathway, along with a discussion on other Shh pathway inhibitors being developed.