Background: Cancer driver events occur as a result of chromosomal rearrangements. There are several examples where targeted inhibition of the resulting fusion produces dramatic clinical response. For example, the EML4-ALK fusion in non-small cell lung cancer (NSCLC). Other ALK fusions have been described in NSCLC and other diseases including the NPM-ALK fusion in anaplastic large cell lymphoma (ALCL). The efficacy of crizotinib and other ALK inhibitors are being investigated in these diseases. ALK is also subject to activation via mutation and sensitivity to crizotinib is reported in ALK mutation positive neuroblastoma. Finally, crizotinib has activity not only against ALK, but also against ROS1, MST1R and MET. ROS1 fusions have been found in NSCLC and glioblastoma, and MET amplification events in gastric adenocarcinoma identify additional settings that may benefit from crizotinib treatment. Methods: To further understand the full therapeutic potential of Crizotinib, we undertook a genomic survey of ALK, ROS1, MET and MST1R across 1,000’s of patients from the The Cancer Genome Atlas (TCGA) and Oncomine. Results: We confirmed the presence of EML4-ALK fusions in both lung and colorectal cancer (CRC), and also identified a novel ALK fusion in CRC. ALK hotspot mutations and focal amplifications were confined to neuroblastoma, as previously described. Our survey of ROS1 identified rare novel fusions in NSCLC and glioblastoma, and high-level amplifications in liposarcoma (2%) and rarely in breast cancer (0.2%). No fusions were identified for MET, however high-level amplifications were observed in 1-5% of papillary renal cell carcinoma, the intestinal subtype of gastric adenocarcinoma, oliogodendroglioma, glioblastoma and lung adenocarcinoma. Hotspot mutations were frequently observed in squamous head and neck (11%), and more rarely in hepatocellular carcinoma, small cell lung and ovarian cancers. Conclusions: These results leverage all available genomic profiling data to provide a broadened scope of therapeutic opportunity for inhibitors like crizotinib. With the growing availability of next-generation sequencing, such surveys can support hypothesis-driven development of targeted therapies.