Introduction: Non-melanoma skin cancers (NMSC) mainly comprise two different entities: basal cell carcinoma (BCC) and squamous cell carcinoma (SCC); beneath these two entities, Merkel cell carcinoma, adnexal tumors, dermatofibrosarcoma protuberans, angiosarcoma, and cutaneous lymphoma belong to NMSC. These rare skin tumors are not the topic of this review.BCC and SCC are the most common cancers diagnosed in humans. The preferred treatment is surgery, which in most cases is curative. Although a high recurrence rate is seen, these cancers rarely metastasize. Therefore, systemic treatments were not a priority for these patients. It is long known that the abnormal activation of Hedgehog and epidermal growth factor receptor pathways were involved in BCC and SCC. In the last decade, metastatic disease became an important area of research, mostly because new therapies that targeted components of these two pathways became available.Areas covered: Here we cover the available therapeutic options for patients diagnosed with BCC and SCC, focus on systemic and targeted therapies.Expert opinion: BCC and SCC are common cancers, with good prognosis. More than the metastatic disease, advanced local disease and recurrent disease pose clinicians a great challenge. Albeit there are promising results with targeted therapies, resistance development has already been described.