Nowadays, chronic lymphocytic leukemia (CLL) is considered as a prototypic antigen-driven lymphoma, with antigenic stimuli from the microenvironment promoting tumor outgrowth. Antigen recognition is a function of both the clonotypic B cell receptor immunoglobulin (BcR IG) and various other immune sensors, e.g., the Toll-like receptors. The critical role of BcR IG-mediated signaling in CLL development and evolution is underscored by the following: the disease-biased IG gene repertoire; the subdivision of CLL based on the somatic hypermutation load of the BcR IG into two broad categories with vastly different prognosis and eventual outcome; the existence of subsets of cases with distinct, quasi-identical (stereotyped) BcR IGs; and the clinical efficacy of novel therapeutics inhibiting BcR signaling. Here, we trace the immunogenetic evidence for antigen selection in CLL and also consider the types of implicated antigens as well as the immune signaling pathways relevant for CLL ontogeny and clonal progression.