Most patients with chronic lymphocytic leukemia are diagnosed at an early stage, when traditional staging systems fail to distinguish those with an aggressive disease course from those with an excellent prognosis. This failure underscores the need for better prognostic markers. Although many markers have been explored, this review focuses on the newer and most clinically relevant markers: cytogenetic aberrations, zeta-associated protein 70, immunoglobulin mutational status, and CD38 expression. Although these markers have been shown to predict outcomes for groups of patients, individual patients may have a variable course; therefore, the outcome for any one patient remains hard to predict. To date, no study has shown a benefit from early cytotoxic therapy for any subgroup of patients with chronic lymphocytic leukemia.