Renal cell carcinoma (RCC) accounts for approximately 3% of all new cancer diagnosis every year. RCC arises from the renal epithelium and represents 85% of all kidney tumors. According to histology, these neoplasms are divided into the following types: clear cell, papillary, chromophobe, oncocytoma, collecting duct, and unclassified. Approximately, 75% of RCCs are of the clear cell type and in recent years, there have been substantial advances in the understanding of its molecular biology leading to the development of effective treatments. However, there is still an area of uncertainty with regard to non-clear cell histologies. Scarce studies have been conducted testing different drugs in this patient population. Thus, most of the evidence comes from small phase II trials, retrospective analysis, or expanded access programs. Recent insights in the molecular basis of these tumors have opened a promising research field. Molecules targeting mammalian target of rapamycin, epidermal growth factor receptor, c-MET, vascular endothelial growth factor, and platelet-derived growth factor are among some of the promising drugs tested in this setting. This article reviews the mechanisms of disease on RCC and summarizes treatment options with a particular focus on patients with non-clear cell tumors.