Although small molecule inhibitors that target the aberrant signaling pathways and molecular defects of chronic lymphocytic leukemia (CLL) result in improved survival benefits vs. traditional chemoimmunotherapy or chemotherapy, treatment resistance may result later, reflecting the intrinsic tumor heterogeneity, persistence of the leukemic clone, and presence of the tumor microenvironment, which supports the survival of the disease clone. Patients with CLL have immune-related abnormalities in T lymphocyte subset composition, immune synapse formation, and other immune dysregulations. Cellular interactions between the disease clone and its microenvironment provide therapeutic opportunities to target these tumor pathogenesis pathways, potentially improving the patient's immune functions and clinical outcomes of targeted therapies. At present, despite the lack of response of immune checkpoint inhibitors in CLL, they showed promising efficacy in patients with Richter transformation. Together with CD19-targeted chimeric antigen receptor-modified T cell (CAR-T) therapy, novel bispecific antibodies and other immunotherapies are being investigated to improve survival outcomes for patients with relapsed or refractory (R/R) CLL, as exemplified by epcoritamab, a bispecific antibody that recently demonstrated initial efficacy in R/R CLL and in patients in high-risk CLL subgroups, including those with TP53 aberrations and unmutated genes that encode immunoglobulin variable heavy chain region (IGHV). Furthermore, to address the immune escape of cancer cells and issues that impact the durability of single-targeted T cell-redirected therapies, novel strategies such as trispecific antibodies and combination therapies are being investigated to increase tumor specificity or immune cell activation. In summary, there is emerging evidence that immunotherapies may counteract the immunosuppressive microenvironment of CLL, improve clinical responses, decrease the risk of infection, and overcome treatment resistance.