After unprecedented successes in B-cell malignancies, chimeric antigen receptor T cells have recently been investigated for the treatment of multiple myeloma. Chimeric antigen receptor targeting T cells B-cell maturation antigen (BCMA) on malignant plasma cells have led to impressive clinical responses in recent trials. However, BCMA-negative relapses have been observed, supporting the need for complementary treatment strategies. Here, we explored the feasibility of targeting CD138 (syndecan-1), a surface marker expressed on both normal and malignant plasma cells. We showed that T cells from both healthy donors and from multiple myeloma patients, when transduced with a CD138-specific chimeric antigen receptor, can eliminate tumor cell lines and primary myeloma cells both in vitro and in vivo. CD138 is also expressed by putative myeloma stem cells identified by Hoechst staining, and these cells can be eliminated by CD138-specific chimeric antigen receptor T cells. Preclinical analyses did not identify any on target off tumor cytotoxicity against normal epithelial or endothelial cells, further supporting the rationale for the use of adoptively transferred CD138-specific chimeric antigen receptor T cells for the treatment of patients with relapsed/refractory multiple myeloma.