While metabolic deregulation is an established hallmark of cancer, metabolic dynamics underlying androgen receptor-expressing prostate cancer (ARPC) and aggressive variant prostate cancer (AVPC)—two forms of lethal castration-resistant prostate cancer—have yet to be defined. In their study on page 51, Mossa and colleagues investigated ARPC and AVPC metabolism using patient sample-derived datasets and xenografts, as well as cell lines. The cover image depicts a multiphoton micrograph of PC3 prostate cancer cells in a mouse tibia, where DAPI-stained PC3 cells fluoresce red and bone collagen is white owing to second harmonic generation. The authors found that ARPC tends to rely on oxidative metabolism, while AVPC is more glycolytic. Correspondingly, complex I inhibitor IACS-10759 slows ARPC growth in vitro and in vivo, while not affecting AVPC growth in vitro and inhibiting AVPC growth in bone but not in other sites in vivo. This article is also Highlighted on page 1.