Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin's lymphoma (NHL). 30 ~ 40% of DLBCL patients were resistant to the standard R-CHOP regimen or recurrence after remission. It is currently believed that drug resistance is the main cause of the recurrence and refractory of DLBCL (R/R DLBCL). With the increased understanding of DLBCL biology, tumor microenvironment and epigenetics, some new therapies and drugs like molecular and signal pathway target therapy, chimeric antigen receptor (CAR) T-cell therapy, immune checkpoint inhibitors, antibody drug-conjugate and tafasitamab have been used for R/R DLBCL. This article will review the drug resistance mechanism and novel targeted drugs and therapies of DLBCL.