More than twenty years of research on cellular immunotherapy has recently resulted in the development of genetically-modified T cell products that express synthetic chimeric antigen receptor (CAR) with specificity toward the cell-surface tumor antigens. Recent studies have demonstrated promising response rates after infusion of these cells in patients with B-cell precursor and mature B-cell neoplasms, including acute lymphoblastic leukemia, diffuse large B-cell lymphoma, and plasma cell myeloma. Given the satisfactory evidence of their outstanding therapeutic benefit, CD19-targeted CAR T cells have become the first genetic engineering element approved by the United States Food and Drug Administration to treat patients for whom other promising options are unavailable. While clinicians are widely using CAR T-cell therapies, the two most common toxicities are cytokine-release syndrome and CAR T cell-related neurotoxicity/encephalopathy syndrome. Moreover, some studies have explained that the relapse after receiving CAR T-cell therapy is caused by acquired resistance due to genetic mutation or splicing variants, leading to the loss or diminished surface expression of the target molecule in neoplastic cells. To overcome these caveats and achieve therapeutic success, restless efforts are ongoing toward the development of next-generation CAR T cells with more sophisticated design.