There is an urgent need for noninvasive molecular tests to assist in the detection of cancers. There is additionally a need for prognostic and predictive markers and for monitoring for disease recurrence. The improved understanding of molecular features of common cancers and the availability of genetically engineered mouse models (GEMMs) of cancer have resulted in increased interest in the application of mouse models to the discovery of cancer biomarkers relevant to humans. Unlike humans, mouse models allow sampling of tumor and host tissues and biological fluids at defined time points in the course of tumor development and progression. Interrogation of the genome, transcriptome, proteome, and metabolome of tumors and biological fluids from mouse models engineered to recapitulate human tumors makes it possible to apply a systems approach to define biomarker signatures from the earliest stages of tumor development to advanced stages and metastasis and signatures reflective of driver genes and pathways.