The primary site of prostate cancer metastasis is bone, which is associated with significant morbidity and mortality; yet there are few curative treatment options, in part due to the characteristic heterogeneity of prostate cancer. Our studies employ novel in vivo models and advanced technological approaches to elucidate tumor cell intrinsic and tumor cell extrinsic mechanisms underlying bone metastasis and response to drug treatment. Our studies may provide new insights that will fine-tune treatment with metastatic prostate cancer.