OVERALL ABSTRACT Although we have made great strides in our understanding of the biology and treatment of chronic lymphocytic leukemia (CLL) over the past decade, Richter's syndrome (RS) or the transformation of CLL to aggressive lymphoma remains an area of unmet need in the clinical care of CLL patients. The challenges presented by RS mandate large-scale interdisciplinary approaches to more completely link genomic and protein-level features with cellular behavior so that more precise and sensitive molecular-based diagnostic schema and more effective treatments for this devastating disease can be devised. Our hypothesis is that genomic and epigenomic alterations define the trajectory from CLL to RS and that distinct subtypes of RS exist, leading to distinct phenotypic behaviors. Our approach to address the challenge of understanding RS builds from the strengths of our highly interactive and multi-disciplinary program in CLL research. Over the last funding period, we have succeeded in generating the largest CLL `map' to date, integrating genetic, transcriptomic and methylome data with clinical annotation from over 1000 CLL samples to discover clinically meaningful subtypes of disease and novel driver alterations. From this information, we have also generated genetically-faithful CLL mouse models reflective of human disease, defined patterns of disease kinetics and therapeutic resistance, and identified new therapeutic vulnerabilities. Over the next 5 years, we will leverage the new resources generated by our Program, ranging from computational to functional, genetic and phenotypic readouts, to confront the challenge of understanding and addressing RS. Thus, our vision is that we will enact a precision approach for understanding the distinct biology of disease transformation and the subtypes of disease, and perform functional analyses of responses to small molecules and immunotherapy agents, that could be integrated and lead to a paradigm shift in the detection and treatment for this disease. These highly translational initiatives are strongly supported by the expertise of the Core Leaders. Our overarching goal is thus to revolutionize the clinical outcomes of patients with this devastating disease and to utilize the information discovered from this Program to motivate the rational design of the next generation of personalized and even curative therapies for RS.