Chronic lymphocytic leukemia (CLL), an indolent B-cell malignancy frequently diagnosed in the elderly, is characterized by the relentless accumulation of CD5+ monoclonal B cells that proliferate in the appropriate tissue microenvironments. Despite many advances achieved by molecular and functional studies, our knowledge of the reciprocal relationship between the CLL cell and its microenvironment at the tissue level is still largely incomplete. In this review we present the relevant current information on the tissue microenvironmental features of CLL, focusing on the events that appear to occur in the lymph node. Special attention is devoted to analyzing the properties of both neoplastic and nonneoplastic bystander cells within proliferation centers, the mysterious structures that likely represent the actual proliferative compartment.