Pivotal clinical trials of B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed/refractory multiple myeloma (MM) resulted in remarkable initial responses, which led to a recent FDA approval. Despite their success, durable remissions continue to be low, and the predominant mechanism of resistance is loss of CART-cells and inhibition by the tumor microenvironment (TME). MM is characterized by an immunosuppressive TME with an abundance of cancer-associated fibroblasts (CAFs). Using MM models, we studied the impact of CAFs on CART-cell efficacy and developed strategies to overcome CART-cell inhibition. We demonstrated that CAFs inhibit CART-cell anti-tumor activityand promote MM progression. CAFs express molecules such as fibroblast activation protein and SLAMF7, which are attractive immunotherapy targets. To overcome CAF-induced CART-cell inhibition, we generated CART cells targeting both MM cells and CAFs. Our dual-targeting CART-cell strategy significantly improved the effector functions of CART cells. We demonstrate for the first time that dual targeting both malignant plasma cells and the CAFs within the TME is a novel strategy to overcome resistance to CART-cell therapy in MM.