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Prostate cancer has traditionally been diagnosed using systematic transrectal ultrasound-guided biopsy. However, given the inherent nature of sampling, a negative biopsy does not exclude clinically significant prostate cancer (csPCa), and continued controversy exists in the optimal management following initial biopsy. Numerous avenues for evaluation include multiparametric MRI (mpMRI), use of molecular biomarkers, repeat biopsy, and observation.mpMRI has shown promise in guiding further biopsy management: for individuals with identified target lesions, increased accuracy and detection using combination targeted and systematic sampling has been repeatedly demonstrated in the literature as an effective strategy. For those with negative MRIs and/or negative biomarker (blood, urinary, tissue) studies, increasing evidence has suggested that these individuals may be able to avoid biopsy altogether, albeit at a small risk of missing csPCa. Observation should be based on an individual's risk of csPCa versus their competing health risks, and saturation biopsy reserved for rare cases with high clinical suspicion.Management following an initial negative prostate biopsy requires careful discussion with the patient, their risk tolerance, and threshold for intervention. Although subject to availability, mpMRI and molecular biomarkers may better risk stratify patients, identify target lesions, and in certain cases, spare biopsy altogether.