Cancer accounts for millions of deaths annually and is a major threat to public health. Large sequencing efforts have helped uncover genetic events that drive cancer development. These studies have identified novel cancer biology and ultimately led to the development of new therapies. Despite these advances, tumors with similar genetic alterations often have highly heterogenous outcomes. Given this, identifying, characterizing, and subsequently targeting the molecular drivers of aggressive tumors is a significant unmet need in cancer research. Using -omics data and molecular biology tools, we sought to identify novel biology driving tumors with elevated genomic instability. These analyses helped us identify that the transcription factor MYB proto-oncogene like 2 (MYBL2) drives aggressive, genomically unstable lung adenocarcinomas. Subsequent pan-cancer analysis extended our initial results and allowed us to define a new cohort of tumors characterized by replicative instability (RIN). In vitro experimentation allowed us to discover that MYBL2 controls all levels of the cellular response to replication stress. Lastly, -omics guided small molecule inhibitor screens helped uncover novel therapeutic vulnerability nodes and chemo-sensitization combinations for the treatment of MYBL2 High/RIN+ disease.