Chronic lymphocytic leukemia (CLL) has a variable clinical course. Some patients have stable disease while others progress and require treatment. Levels of several cluster of differentiation (CD) antigens are known to correlate with prognosis and may be used to stratify patients according to risk. In this review, we summarize current information on surface CD antigens found on CLL, their pathological significance and their detection using CD antibody microarrays. The use of extensive immunophenotypic patterns or surface profiles as disease signatures for CLL subclassification, prognosis and patient management is discussed with a focus on triaging patients with CLL with progressive disease.