Overcoming resistance to endocrine therapy is the most intensive research area in estrogen receptor (ER)-positive breast cancer. A strategy to restore endocrine sensitivity using molecular-targeted drugs such as mammalian target of rapamycin inhibitor everolimus along with endocrine therapy has already been used as a treatment option after the progression of previous aromatase inhibitor therapy. Phase II/III clinical trials of several signal pathway inhibitors and cyclin-dependent kinase 4/6 inhibitors are underway. In addition, a randomized phase II trial of the histone deacetylase inhibitor entinostat showed interesting findings. In this review, we summarize the mechanistic principles of combination therapy of molecular-targeted drugs with endocrine therapy by using a hybrid car model.