Background/Objectives: Multiparametric-Magnetic Resonance Imaging(mp-MRI) presents the ability to detect clinically significant cancer, aiming to avoid biopsy if the results are negative or target an abnormal lesion if a suspected lesion of the prostate is found. Recent guidelines recommend the performance of 12 standard biopsies along with 3 to 5 targeted biopsies in suspected prostate lesions, depending on the size of the prostate lesion. In addition, prostate biopsy can be performed by either the transperineal or the transrectal approach. The aim of this comprehensive review is to highlight the role of both standard and targeted MRI/Ultrasound (US) fusion transperineal biopsy (TPB) in the diagnostic approach of prostate cancer cases, to report its diagnostic efficacy and complication rates and to suggest the promising usage of MRI/US fusion TPB in the future. Methods: A comprehensive review of the existing literature, including systematic reviews, meta-analyses, and clinical guidelines, was conducted to compare the efficacy and safety of transperineal and transrectal approaches in prostate cancer detection. Special emphasis was placed on mp-MRI-guided targeted biopsy and its combination with systematic sampling. Results: Prostate biopsy via the transperineal approach is related to increased detection rates, especially for anterior lesions, and decreased infection risk compared to the transrectal approach, while complication rates (hematuria, hemospermia, etc.) remain similar. Due to lower infection rates via the transperineal route, the performance of prostate biopsy using the transperineal approach is strongly recommended. Finally, transperineal fusion MRI/US biopsy can be valuable for repeat biopsies in patients who had an initial negative biopsy or for the follow-up of patients that undergo active surveillance. Conclusions: MRI/US fusion-guided TPB represents a significant advancement in prostate cancer diagnostics, combining improved precision with reduced infection risks. Although TPB presents higher detection rates for anterior prostatic lesions and lower post-biopsy infection rates, there is no significant difference in cancer detection rates compared to TRB. Targeted training and investment may reduce long-term expenses of TPB by lowering hospitalizations, antibiotic usage, and related costs. Future research should further refine this approach and explore its integration with emerging technologies like artificial intelligence for enhanced lesion targeting and diagnostic accuracy.