Recent therapeutic advances in chronic lymphocytic leukemia (CLL) are reflected by high response rates in most subsets of patients. However, refractory disease remains a problem, and virtually all of even the most sensitive tumors eventually recur. Therefore, ongoing efforts aim at the development of optimized interventional designs that more specifically target the strong pro-survival signature of the transformed B cell. Stimuli from the CLL microenvironment are considered the predominant force that sets this high anti-apoptotic threshold. We introduce here our concept that the oncogene T-cell leukemia 1A (TCL1A), which induces CLL-like disease in transgenic mice, significantly enhances such milieu-derived signaling, propagates associated resistance, and therefore represents a targetable pathway in CLL. We discuss inhibitory strategies that are based on TCL1A's activation of the growth modulating kinase AKT and on influences that regulate TCL1A expression. Respective preliminary data indicate that differential response categories of CLL exist. Future studies will test TCL1A's inherent predictive information.