The discovery of mutations in the BRAF signaling molecule in a large proportion of cutaneous melanomas immediately suggested the prospect of effective therapies for this disease. The most appealing initial target has been BRAF itself, as most mutations involve a single residue in the kinase domain of the protein. But the identification of the high mutation rate in this signaling intermediate also suggests that other molecules up- and downstream of BRAF might be productively targeted. Indeed, several receptor tyrosine kinases, as well as RAS, are mutated in a small number of melanoma cases. Moreover, genetic alterations in the phosphotidylinositol-3-kinase (PI3K) pathway, especially in PTEN, suggest that this route also poses opportunities for therapeutic exploitation. We will review here the genetic evidence suggesting the utility of targets on these pathways. We will also summarize the recent clinical data that have accumulated from initial trials designed to test BRAF inhibition and targeting of other molecules. Finally, we provide an overview of molecules entering the clinic and soon to be tested in clinical studies, as well as strategies for their employment as monotherapy and in combinations.