The molecular-targeted agent sorafenib is the first anticancer agent able to slow the progression of advanced/metastatic renal cell carcinoma, a tumor that was formerly refractory to conventional therapy. Experience from everyday clinical practice and investigations exploring the suitability of this agent for patients with harmful pathological conditions has extended the use of sorafenib to other settings of renal cell carcinoma and to particular risk populations. The aim of this review is to provide evidence on the most effective and safe use of sorafenib. The review pays particular attention to patients who have several comorbidities, such as impaired renal and cardiac function, and older patients whose frailty due to impaired organ function necessitates the most careful administration of targeted antineoplastic agents.