Medical therapy represents an alternative treatment approach that can be considered for some forms of non-melanoma skin cancer (NMSC). In selected cases, topical treatments are preferable to invasive procedures, especially in the case of multifocal lesions, unclear lesion edges, risk of keloids, surgical risk factors and localization in some areas such as the face and décolletage, as the cosmetic outcomes are generally excellent. In the case of advanced and metastatic NMSC, molecularly targeted therapy represents a reasonably promising alternative to classical cytotoxic chemotherapy. Based on the existing literature and the authors’ experience, this paper analyzes and discusses the mechanisms of action, formulations, official and off-label indications, efficacy, side effects and contraindications of medical treatments that are utilized in the treatment of NMSC, including 5-fluorouracil, imiquimod, diclofenac, ingenol mebutate, resiquimod, piroxicam, dobesilate, betulinic acid, vismodegib, cetuximab, gefitinib and cytotoxic chemotherapy.