The generation of genetically engineered mouse models (GEMMs) that mimic breast cancer in humans provides new tools to investigate mechanisms of drug resistance in vivo. The advantages are manifold: inbred mice do not have the genomic heterogeneity seen in patients; mammary tumors are superficial and therefore easily accessible for measurement and sampling pre- and posttreatment; tumors can be transplanted orthotopically into syngeneic, immunocompetent animals; and tumor cells can be modified in vitro (e.g., gene overexpression, shRNA knockdown, insertional mutagenesis) prior to transplantation. Here, we provide an overview with experimental details of various approaches to study mechanisms of drug resistance in GEMMs for breast cancer.