Tumor microheterogeneity is common and subclones in primary tumors are potential mediators of tumor progression. Laser capture microdissection was used to isolate foci of residual tumor (purple and green) that remained after regression of the bulk tumor (red) in radical prostatectomy specimens from patients with prostate cancer treated for 6 months with neoadjuvant intensive androgen deprivation therapy. Whole exome sequencing identified foci-specific oncogenic alterations, including losses of RB1, BRCA2, or PTEN, indicating that the tumor prior to therapy contained subclones that were castration-resistant by distinct mechanisms. These subclones may evolve further and may be the origin of metastatic castration-resistant prostate cancer, and their early detection may allow for more effective adjuvant therapy. For details, see article by Sowalsky and colleagues on page 4716.