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Summary: Cancer is often seen as a disease of mutations and chromosomal abnormalities. However, some cancers, including pediatric rhabdoid tumors (RTs), lack recurrent alterations targetable by current drugs and need alternative, informed therapeutic options. To nominate potential targets, we performed a high-throughput small-molecule screen complemented by a genome-scale CRISPR-Cas9 gene-knockout screen in a large number of RT and control cell lines. These approaches converged to reveal several receptor tyrosine kinases (RTKs) as therapeutic targets, with RTK inhibition effective in suppressing RT cell growth in vitro and against a xenograft model in vivo. RT cell lines highly express and activate (phosphorylate) different RTKs, creating dependency without mutation or amplification. Downstream of RTK signaling, we identified PTPN11, encoding the pro-growth signaling protein SHP2, as a shared dependency across all RT cell lines. This study demonstrates that large-scale perturbational screening can uncover vulnerabilities in cancers with “quiet” genomes. : Using a diverse set of rhabdoid tumor cell lines and both small-molecule and CRISPR-Cas9 gene-knockout screening, Oberlick et al. find high expression and dependency upon a wide range of receptor tyrosine kinases (RTKs) and SHP2 downstream. These RTK inhibitors are also effective against a rhabdoid tumor mouse model. Keywords: rhabdoid tumors, SMARCB1, high-throughput drug screening, genome-wide CRISPR screening, receptor tyrosine kinase, PTPN11