Over the past decade, the sextant biopsy technique has emerged as the standard of care in the detection of prostate cancer. This technique is easy to learn and well tolerated by patients and has a major complication rate of <1%. However, limitations in cancer detection have been appreciated, particularly a false-negative rate approaching 25%. This high failure rate has led investigators to refine biopsy techniques to improve cancer detection. Intuitively, increasing the total number of cores should improve cancer detection. However, the optimal core number has yet to be defined. Confounding factors include variability of prostate size, tumor volume, and tumor location. Currently, a new standard is emerging prescribing a minimum of eight cores, of which at least three are directed at the lateral aspect of the peripheral zone. These additional biopsies appear to enhance cancer detection by about 15%. The improved yield is most pronounced among patients with a serum prostate specific antigen concentration between 4 and 10 ng/mL and larger gland volume (>50 cc). These additional biopsies may decrease the need for repeat biopsies. In the meantime, strategies are being developed for the optimal technique of repeat biopsies among patients with persistent clinical suspicion in the setting of a prior negative biopsy. Currently, recommendations include increasing the biopsy number to a minimum of 10 cores, including sampling of the lateral peripheral and transition zones.