Therapeutic outcomes in chronic lymphocytic leukemia (CLL) have improved markedly with the introduction of potent chemoimmunotherapy regimens capable of regularly debulking the disease to a state of complete remission. However, current combinations are reaching the limits of tolerability and effectiveness. As the major toxicities of treatment are myelosuppression and opportunistic infections, the choice of additional agents to add to current combinations must focus on agents with reduced propensity to these complications, as well as agents that have novel mechanisms of action distinct from DNA damage. In addition, patients with comorbid conditions have not benefited from recent developments in combination treatment due to poor tolerance of chemoimmunotherapy regimens. Therefore, we seek to review the mechanism of activity and therapeutic results of the most promising novel agents in CLL, in order to determine how these agents may be best incorporated into future treatment algorithms of both younger/fit patients and patients with comorbidities.