Over the past 6 years, a number of agents, all mechanistically different, have been approved with a statistically significant survival benefit as monotherapy for treatment of metastatic castration resistant prostate cancer (mCRPC).  Despite these advances, however, the disease remains fatal and is the second leading cause of cancer specific death in men over the age of 50 years old in the United States.  This presentation will focus on the heterogeneity of prostate cancer, review the role of the androgen receptor (AR) in disease progression and discuss molecular mechanisms and mutations that result in treatment resistance.