Background: Malignant rhabdoid tumors (MRTs) are rare, aggressive pediatric solid tumors characterized by a 22q11 chromosome rearrangement that inactivates the SMARCB1 gene. Outcomes remain poor despite multimodality treatment. MRTs are among the most genomically stable cancers and lack therapeutically targetable genetic mutations. We used the Virtual Inference of Protein-activity by Enriched Regulon analysis (VIPER) algorithm to computationally infer protein activity from MRT whole transcriptomic data available in the TARGET database to identify candidate non-genetically encoded vulnerabilities. This approach identified markedly aberrant activation of the nuclear export protein Exportin-1 (XPO1) in MRTs compared to other tumor types. We hypothesized that MRTs may be dependent on high XPO1 activity and this dependence can be co-opted as a novel non-oncogene directed therapeutic approach using the XPO1 inhibitor selinexor. Methods: A panel of 6 MRT and 3 atypical teratoid/rhabdoid tumor (ATRT) cell lines were used for in vitro studies. Two patient-derived xenograft (PDX) mouse models of MRT were treated with selinexor to determine anti-tumor effects. Results: All MRT cell lines demonstrated marked baseline activation of XPO1. The median IC₅₀ following 72 hour selinexor treatment was 200 nM (IQR 175-435 nM) for MRT, 460 nM (IQR 400 nM-1.4 μM) for ATRT and 1.1 μM (IQR 580 nM-1.4 μM) for 5 non-MRT cell lines. There was a correlation between inferred XPO1 activity and IC₅₀ with cell lines with the highest inferred activity being the most sensitive to selinexor. Treatment with selinexor in vitro led to cell cycle arrest and induction of apoptosis in MRT cell lines. Post-perturbation RNAseq of selinexor treated cell lines with VIPER dynamic protein activity inference demonstrated decreased activity of XPO1, SWI/SNF complex proteins, kinetochore regulators and cell cycle regulators. In vivo treatment of two MRT PDXs with oral selinexor for 15 days significantly inhibited tumor growth in both models (p < 0.0001 and p = 0.0002). Conclusions: Selinexor demonstrates efficacy in preclinical models of MRT. These results supports further investigation of selinexor in a phase II study in children with MRT.