Genetically targeted T cells promise to solve the feasibility and efficacy hurdles of adoptive T-cell therapy of cancer. Selecting a target expressed in multiple-tumor types and required for tumor growth would widen disease indications and prevent immune escape due to the emergence of antigen-loss variants. The adhesive receptor CD44 is broadly expressed in hematological and epithelial tumors, where it contributes to the cancer stem/initiating phenotype. In this study, silencing of its isoform variant 6 (CD44v6) prevented engraftment of human AML and MM cells in immunocompromised mice. Accordingly, T cells targeted to CD44v6 by means of a chimeric antigen receptor containing a CD28 signaling domain mediated potent antitumor effects against primary AML and MM, while sparing normal hematopoietic stem cells and CD44v6-expressing keratinocytes. Importantly, in vitro activation with CD3/CD28 beads and IL-7/IL-15 was required for antitumor efficacy in vivo. Finally, co-expressing a suicide gene enabled fast and efficient pharmacological ablation of CD44v6-targeted T cells and complete rescue from hyper-acute xenogeneic graft-versus-host disease modeling early and generalized toxicity. These results warrant the clinical investigation of suicidal CD44v6-targeted T cells in AML and MM.