The improvements in the knowledge of the underlying biology of renal cell carcinoma (RCC) has led to consider this disease as a group of different entities characterized by their pathological phenotype, and the particular features exhibited in their microenvironment. Non-clear cell RCC (nccRCC) represents a heterogeneous group of kidney cancers showing different genetic, histologic, and morphological characteristics that in turn lead to diverse biologic behaviors. Since nccRCCs are infrequent, they are commonly scarcely represented or excluded from most randomized controlled trials, making data on the efficacy of current treatment options still limited, and the optimal systemic therapeutic schedule for the treatment of advanced stages yet to be defined. This review summarizes the available literature regarding the salient morphogenetic features encountered among the different nccRCC subtypes, and updates the evidence provided by the current studies reporting on the efficacy of targeted therapy in this kind of tumors.