Rituximab, a chimeric mouse/human monoclonal antibody (mAb) targeting CD20, has proven to improve treatment outcomes in a number of B-cell malignancies, including chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (FL). Rituximab in combination with standard chemotherapeutic regimens (R-CHOP) has proven to be the current standard treatment, with successful outcomes in a larger subset of patients compared to monotherapy. However, in addition to initially nonresponding patients, evidence suggests that many responding patients develop resistance to further treatments. The mechanisms by which monoclonal antibodies target CD20 in vivo are poorly understood, although the implicated mechanisms include the direct induction of apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). The processes of other postulated mechanisms considered to be intracellular antitumor effects are also described in this review. Here we discuss methods for reversing resistance to anti-CD20 antibody therapies via targeting intracellular signaling pathways that regulate resistant factors. With an increased understanding of the underlying mechanisms of resistance, more effective new approaches may be developed for early diagnosis and therapeutic responses.