Advanced basal cell carcinoma (aBCC) encompasses locally advanced BCC (laBCC) and metastatic BCC (mBCC), two variants of BCC with a limited prevalence worldwide. Treatment of aBCC is still very challenging for the lack of randomized controlled trials/guidelines and the scarcity of available therapeutic options. Based on current data, surgical procedures and radiotherapy are considered the treatments of choice for aBCC although often associated with substantial morbidity and/or deformity. Alternatively, systemic chemotherapy and electrochemotherapy can be used but standardized treatment schedules and randomized clinical trials are not available for both treatments. In recent years, novel tumor-specific and pathogenesis-based molecules have been developed for the treatment of aBCC. A number of clinical trials have recently demonstrated the efficacy and tolerability of vismodegib, the first novel systemic, anti-Smo target cancer therapy for aBCC. Additional molecules currently investigated in phase I-III clinical trials include other Smo antagonists and itraconazole. The contribution of a multidisciplinary team composed of dermatologists, surgeons, oncologists, pathologists, radiologists and radiotherapists is required to deal with the spectrum of issues that emerge from managing patients affected by aBCC.