Inhibition of the hedgehog signaling pathway (HHSP) for the treatment of locally advanced basal cell carcinoma (BCC) and metastatic BCC (mBCC) has produced promising results. Typically, mBCC is not taken into consideration during the workup of a patient with multifocal metastatic disease who has a history of BCC. The objective of the current review, in which the authors evaluated the time from the first BCC diagnosis to metastasis, location of disease, and radiographic features, was to contribute to the general knowledge and awareness among providers, patients, and support groups about mBCC and to provide an outlook for the future of treatments for mBCC. A literature review on mBCC and a review of records from patients with mBCC who presented to Virginia G. Piper Cancer Center Clinical Trials (an oncology clinical trials center) were conducted. The clinical and radiographic findings of 22 patients with mBCC who were evaluated at that center from the initiation of smoothened (SMO) antagonist trials were analyzed along with a review of BCC epidemiology and pathogenesis, the HHSP, and current and future treatments for this rare presentation of the most common malignancy. The results indicated that, in the last 5 years, there has been a plethora of new agents targeting SMO, a key component of the HHSP that, for the majority of patients with mBCC, may be a good match for targeting tumor genetic vulnerability. Like with other targeted therapy for uncommon malignancies, such as chronic myelogenous leukemia and gastrointestinal stromal tumors, the authors anticipate that there will be clinical development of next-generation HHSP inhibitors to combat mBCCs that are nonresponsive to or progress on current SMO antagonists. Cancer 2012. © 2012 American Cancer Society.