Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western World and remains incurable with conventional chemotherapy treatment approaches. CLL has a highly varied clinical course. The substantial clinical variability in the clinical course of CLL has motivated intense efforts at identifying molecular markers that can be used for CLL prognostication. While many such markers have been proposed, few have stood the test of time; this is due to various reasons outlined in detail in this chapter.Of the reasons that have affected the usefulness and broad applicability of CLL biomarkers a few stand out as recurrent: lack of independent effects of individual markers on prognosis; the use of arbitrary cutoffs when using continuous variables; technical challenges in validity, reproducibility, and reliability (classical test characteristics); and lack of marker validation in prospectively identified CLL patient cohorts.Nonetheless, a few useful prognostic markers (CLL interphase FISH, immunoglobulin heavy chain variable region mutation status) have been identified, and others are still in transition to widespread clinical applications (TP53 mutations, SNP array-based elevated genomic complexity).As CLL therapy transitions from genotoxic combination therapies to targeted therapies, it will be of importance to reestablish the usefulness of our current understanding of individual CLL traits in CLL prognosis. Finally, the identification of predictive markers remains important given the established associations of poor response rates with shortened survival and the ongoing need for more personalized approaches in CLL management.