Cancer of the prostate gland is a common but heterogeneous disease requiring individualized risk stratification for optimal clinical management. However, transrectal ultrasonography (US)-guided biopsy-the standard of care for diagnosis of prostate cancer-frequently fails to detect aggressive tumors or provide reliable parameters for pretreatment risk stratification. Multiparametric magnetic resonance (MR) imaging is the most accurate imaging technique for prostate cancer detection and local staging. Recently, different approaches have been developed to allow targeted biopsies of areas that are suspicious for cancer at MR imaging, including direct MR imaging guidance and MR imaging-transrectal US fusion, which can be achieved with cognitive fusion or software assistance. Regardless of the technique used, targeted prostate biopsies have the potential to increase detection of clinically relevant prostate cancer and provide more reliable risk stratification in patients with known cancer. The authors discuss the shortcomings of traditional diagnostic workup for prostate cancer, the rationale for targeted prostate biopsies, the different techniques available for targeting suspicious areas seen at MR imaging, and the clinical contexts in which targeted prostate biopsies might be useful. In addition, they discuss opportunities and challenges associated with MR imaging-transrectal US fusion biopsy, as well as questions that need to be addressed before formal incorporation of this technique into practice guidelines.