Renal Medullary Carcinoma (RMC) is an aggressive malignancy that affects young black individuals with sickle cell trait. No effective treatment is available, resulting in an ominous clinical course, with overall survival averaging less than four months. We report rearrangement of the ALK receptor tyrosine kinase in a pediatric case of RMC harboring a t(2;10)(p23;q22) translocation. Mass spectrometry-based proteomic evaluation identified a novel ALK oncoprotein in which the cytoskeletal protein vinculin (VCL) was fused to the ALK kinase domain. The resulting VCL-ALK fusion does not contain known self-association domains, but includes the talin binding domains of vinculin. We demonstrate coprecipitation of strongly tyrosine phosphorylated talins with the VCL-ALK oncoprotein, suggesting that ALK oncogenic crossphosphorylation is mediated by interactions between neighboring VCL-ALK proteins on a talin scaffold. This report widens the spectrum of ALK-related tumors and ALK fusion partners, and provides a rationale for treating RMC with targeted ALK inhibitors. © 2010 Wiley-Liss, Inc.