Multiple myeloma (MM), characterized by an abnormal proliferation of plasma cells, accounts for 10 %–15 % of hematological tumors [1]. While the survival of MM patients has been greatly prolonged by novel agents like proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs) and monoclonal antibodies (mAbs), the rates of disease recurrence and drug resistance remain high [2,3]. At present, MM cannot be cured, with a median survival of 7–10 years and even less than 3 years in the high-risk population [4]. Molecularly targeted drugs are promising weapons to inhibit the proliferation and induce the apoptosis of MM cells via targeting key signaling pathways or molecular targets [5]. Through genetic engineering in T cells, chimeric antigen receptor T (CAR-T) cell therapy allows to recognize and attack MM cells carrying specific antigens, showing a pronounced efficacy in treating relapsed/refractory multiple myeloma (RRMM) [6,7]. The harsh tumor microenvironment (TME), immune escape and T-cell depletion in MM patients, however, greatly hinder the performance of CAR-T cell therapy in achieving a long-term remission [8]. A combination of molecularly targeted therapy with CAR-T cell therapy has been extensively analyzed for its potential in treating MM and overcoming the resistance [9]. For instance, venetoclax, known for its selective inhibition on Bcl-2, significantly fortifies the efficacy of CAR-T cell therapy for certain subtypes of MM through inducing cell apoptosis [10]. Ibrutinib (a BTK inhibitor) combined with CAR-T cell therapy obviously improves the TME of MM [11]. The present review thoroughly described the applications and prospects of molecularly targeted drugs combined with the CAR-T cell therapy in treating MM, thus providing references for its wider application.