Malignant cells are able to suppress host immune responses in an effort to avoid immune detection in vivo. Tumor-induced immunosuppression can be achieved at the molecular, cellular, and/or physiological levels. Herein the contribution of immune-tolerant genes and regulatory cells to immunosuppression related to alterations of T-cells and antigen-presentation is reviewed. Furthermore, key advances in countering tumor-induced immunosuppression are described in reference to immune evasion mechanisms used by chronic lymphocytic leukemia (CLL) cells. Lastly, the challenges associated with targeting the tumor microenvironment coupled with the usefulness of immunomodulatory drugs are discussed. This review summarizes select immune evasion tactics orchestrated by the conversation between CLL cells and their microenvironment.