Hormone refractory disease represents a late-stage and generally lethal event in prostate tumorigenesis. Analyses of mouse models have recently shown that the onset of hormone independence can be uncoupled from disease progression and is associated with activation of the phosphoinositide-3 kinase/Akt as well as Erk mitogen-activated protein kinase signaling pathways in the prostate epithelium, which act in part to counterbalance the inhibitory effects of androgen receptor signaling in the prostate stroma. These observations have potential implications for the treatment of patients with hormone refractory cancer and highlight the role of epithelial-stromal interactions for androgen independence. [Cancer Res 2007;67(14):6535–8]