There is currently no cure for advanced prostate cancer. As such, mechanistically novel treatment approaches are needed to improve current clinical outcomes. We and others previously demonstrated that calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2), an upstream kinase of AMP-dependent protein kinase (AMPK), is a promising new therapeutic target for the treatment of advanced prostate cancer. Using a combination of pre-clinical cell and animal models in combination with molecular, genetic, and pharmacological approaches, we have delineated CAMKK2’s cancer cell-intrinsic, pro-tumor mechanisms of action mediated through AMPK and CAMKI. In addition to the above-described cancer cell-intrinsic roles of CAMKK2, we have uncovered novel, cancer cell-extrinsic roles for CAMKK2 in systemic metabolism as well as prostate cancer immunology that we postulate can be exploited for therapy. Finally, we describe the development of next-generation inhibitors of CAMKK2 and look ahead to potential mechanisms of resistance that will need to be considered for the design of rationale treatment combinations and patient selection.