The treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. Here, we identify induction of glucocorticoid receptor (GR) expression as a common feature of drug-resistant tumors in a credentialed preclinical model, a finding also confirmed in patient samples. GR substituted for the androgen receptor (AR) to activate a similar but distinguishable set of target genes and was necessary for maintenance of the resistant phenotype. The GR agonist dexamethasone was sufficient to confer enzalutamide resistance, whereas a GR antagonist restored sensitivity. Acute AR inhibition resulted in GR upregulation in a subset of prostate cancer cells due to relief of AR-mediated feedback repression of GR expression. These findings establish a mechanism of escape from AR blockade through expansion of cells primed to drive AR target genes via an alternative nuclear receptor upon drug exposure. Display omitted •GR induction is a common feature of enzalutamide-resistant prostate cancer•GR expression and activity promote resistance to enzalutamide•GR binds and regulates a subset of AR targets in a enzalutamide-insensitive manner•AR inhibition induces high levels of GR in primed prostate cells Prostate cancer cells that have become resistant to androgen receptor (AR) antagonists escape the AR blockade by turning on expression of the closely related glucocorticoid receptor, which functionally substitutes for AR to drive growth, thus identifying GR as a potential therapeutic target.