Cumulative studies on the dissection of changes in driver genetic lesions in cancer across the course of the disease have provided powerful insights into the adaptive mechanisms of tumors in response to the selective pressures of therapy and environmental changes. In particular, the advent of next-generation-sequencing (NGS)-based technologies and its implementation for the large-scale comprehensive analyses of cancers have greatly advanced our understanding of cancer as a complex dynamic system wherein genetically distinct subclones interact and compete during tumor evolution. Aside from genetic evolution arising from interactions intrinsic to the cell subpopulations within tumors, it is increasingly appreciated that reciprocal interactions between the tumor cell and cellular constituents of the microenvironment further exert selective pressures on specific clones that can impact the balance between tumor immunity and immunologic evasion and escape. Herein, we review the evidence supporting these concepts, with a particular focus on chronic lymphocytic leukemia (CLL), a disease that has been highly amenable to genomic interrogation and studies of clonal heterogeneity and evolution. Better knowledge of the basis for immune escape has an important clinical impact on prognostic stratification and on the pursuit of new therapeutic opportunities.