Background: Serial biopsy is a mainstay of surveillance for patients on active surveillance for prostate cancer. mpMRI targeting has become a standard for targeting lesions during biopsy as it allows for better identification of the dominant lesion (grade and/or volume). It is unclear whether “targeted biopsy” alone reliably identifies the dominant lesion on serial biopsy, thereby obviating the need for systematic biopsy. The aim of this study was to assess whether targeting alone can consistently identify the dominant lesion on serial biopsies for active surveillance. Methods: Participants enrolled in active surveillance with early-stage prostate cancer (PSA <20, cT1-2, GG1 and 2) at diagnosis and underwent two or more MR fusion biopsy sessions that include both systematic and targeted sampling. Timing and frequency of Gleason upgrading were assessed. Grade and sextant location within the prostate were compared between the systematic and targeted cores to determine concordance. Results: Of 619 men who had multiple MR targeted biopsies, 80% were GG 1 at time of diagnosis and 20% were GG 2. Fifteen percent had their first MR fusion biopsy as their diagnostic, 41% on confirmatory biopsy, and 44% on subsequent surveillance biopsy. The highest grade was sampled by MR targeting from 70% to 91% of the time. In a subset of 106 men with GG1 at first MR fusion biopsy and a subsequent MR fusion biopsy within 36 months, Gleason upgrading was detected in 47 men (44%) on the 2^nd MR fusion biopsy. When comparing upgrading between systematic and MRI targeting, 20 men (42%) upgraded inside the target only. Twenty-one men (45%) upgraded on both systematic and MR targeted biopsy. And 6 men (13%) upgraded on systematic biopsy only. Conclusions: In those with serial MR-targeted biopsies, targeting alone identified a majority of upgrading. However, it missed a portion of with upgrading outside the target. This suggests that those on active surveillance, with MR targets, still benefit from systematic biopsies.