As the field of oncology evolves, the management of chronic lymphocytic leukemia (CLL) is transitioning toward targeted therapy and personalized medicine. Healthcare providers are able to identify genetic markers and base therapy on disease genotype, performance status, and comorbidities. Survival has been prolonged through monoclonal antibodies combined with chemotherapy. Genuine personalized treatment is made possible by the targeting of specific pathways which are altered in CLL and identified by genetic testing. The toxicity profiles for novel agents vary from what oncologists may find familiar. To successfully manage CLL, healthcare providers must be up to date on the importance of appropriate risk stratification, treatment selection, side effects, and the importance of patient engagement.