Prostate cancer, unlike other cancers, has been sampled in a non-targeted, systematic manner in the past three decades. On account of the low volume of prostate sampled despite the multiple cores acquired, systematic transrectal (TRUS) biopsy suffered from low sensitivity in picking up clinically significant prostate cancer. In addition, a significant number of cancers of the anterior, lateral peripheral zone, and the apex were missed as these areas were undersampled or missed during this biopsy protocol. Subsequently, the number of cores acquired was increased with special focus given to targeting the previously undersampled areas. These procedures led to an increase in the complication rates as well as detection of more clinically insignificant cancers. The advent of multiparametric magnetic resonance imaging (MRI) and its high intrinsic tissue contrast enabled better detection of prostate cancer. This led to the introduction of MRI-targeted biopsies with either MRI-TRUS fusion or under direct (in-gantry) guidance. MRI-targeted biopsies increased the percentage of positive cores and detection of clinically significant prostate cancers; however, these are expensive, time-intensive, require significant capital investment and operator expertise. This article describes the indications, workflow, complications, advantages, and disadvantages of TRUS-guided biopsy followed by MRI-guided biopsies.