In the recent years, the improved understanding of the biological relevance of angiogenesis as a major cancer hallmark led to the development of a heterogeneous group of agents targeting this key process. Among the anti-angiogenic drugs (including monoclonal antibodies such as Bevacizumab, and other molecules with different mechanism of action, such as the vascular disrupting agents Vadimezan), the tyrosine kinase inhibitors (TKIs, Sorafenib, Sunitinib, Pazopanib, and Axitinib), are commonly thought to inhibit angiogenesis through a most rational and promising approach. In this regard, many tyrosine kinase inibitors, such as Sorafenib, are multi-targeted, which allows for the inhibition of those multiple functional pathways which are considered to be critical for both tumor development and progression. Besides, this multi-targeted activity may theoretically increase efficacy but also toxicity. As a member of this group, Sorafenib has already been approved for the treatment of advanced renal cell carcinoma (RCC) and hepatocellular carcinoma not suitable for locoregional treatment, and it is currently under investigation for advanced non small cell lung cancer (NSCLC), either alone or in combination with other biological/cytotoxic agents.