Prostate-specific antigen testing and prostate biopsy have revolutionized our ability to detect prostate cancer at an early stage. The transrectal ultrasound-guided biopsy procedure has undergone a number of modifications over the past 10 years to meet our goal of early detection of cancer at a curable stage. Biopsy schemes have evolved from lesion-directed biopsies to systematic mapping of the peripheral zone of the prostate, which harbors almost all of the significant tumor foci. An increase in the number of biopsy cores from 6 to 10 (or 12) has resulted in a significant improvement in the detection of clinically localized cancer, without any appreciable increase in the number of indolent cancers. Current biopsy schemes also have enhanced our ability to determine the true prognostic value of pathologic lesions such as high-grade prostatic intraepithelial neoplasia and atypical small acinar proliferation which have been associated with cancer detection in repeat biopsies. I discuss the rationale behind, and the outcomes of, various biopsy strategies. More than 15 years after PSA testing was popularized for early detection, a number of men are presenting for evaluation regarding repeat prostate biopsy for various clinical indications. The indications, biopsy scheme, and cancer detection rates for repeat prostate biopsy are discussed in detail.