Pathologists nowadays are frequently confronted with post-radiotherapy biopsies of the prostate. It is critical to recognize the changes of benign prostatic tissue with radiation effect, which include frequent acinar atrophy, acinar distortion, basal cell hyperplasia, decreased acinar/stromal ratio, and stromal fibrosis. The non-neoplastic irradiated prostate can have nuclear enlargement and bizarre nuclei, changes overlapping or exceeding those commonly seen in prostatic adenocarcinoma. The presence of high-grade PIN adjacent to acini in question favors a cancer diagnosis. Ceratin immunostains, particularly cytokeratin 34ßE12, in conjunction with selected other markers, can help the pathologist determine whether residual cancer is present in the most difficult cases.