Prostatic carcinoma (PCa) is usually a multifocal disease characterized by marked heterogeneity of morphology as well as clinical behavior. Nearly 2/3 of prostates with cancer contain multiple tumor foci and the index or the largest tumor may not necessarily determine the clinical outcome. Autopsy studies show that >50% of men over 50 years of age have histologic evidence of PCa, and these latent tumors are histologically identical to aggressive PCa, but have not progressed or become clinically evident in spite of their histological similarities. Thus, it is very important to rely on the appropriate diagnostic tools to be able to effectively evaluate these patients and provide them with the proper clinical and/or surgical approach, avoiding unnecessary radical therapies that may create needless post-operatory morbidity, including erectile disfunction and urinary incontinence. Ferguson (1930) first described prostate aspiration biopsies using an 18-gauge needle transperineally. In 1937, Astraldi first used transrectal biopsies, Takahashi & Ouchi (1963) used for the first time transrectal ultrasound (TRUS) guided biopsies, and Watanabe in 1967 created the first clinical application of TRUS images. It was until the 1980’s that we went back to the use of transperineal biopsies trying to get access to the whole prostate gland. The first sextant prostate needle biopsy scheme was developed by Hodge et al. in 1989 which consisted of TRUS biopsies taken from the midline, base, mid-gland, and apex. The midline sextant biopsies had a PCa detection rate of 20-30%. However, 25-50% of aggressive PCa remain undetected when using this scheme. Stamey et al. (1995) decided to evaluate the location of PCa in radical prostatectomy specimens and they found that PCa had a higher incidence in the posterior horns of the peripheral zone, suggesting that laterally directed biopsies may improve the detection of PCA; this was confirmed by multiple studies, and are the base for the current recommendation of an extended-biopsy scheme with at least 8-12 cores including lateral biopsies. Furthermore, in 2012 we realized that the prostate volume played a significant role in the sampling of the prostate and recommend an optimization of TRUS biopsies by increasing the needle core sampling based on gland volume, performing TRUS midline sextant biopsies with a modified fan-shaped protocol, as follows: 8 biopsies for prostates ≤15 cc, 14 biopsies for those >15 cc but ≤50 cc, and 14-20 for those >50 cc. However, current TRUS biopsies are still not able to detect approximately 30% of clinically aggressive PCa, mainly due to the posterior (rectal) approach of the prostate, which usually misses high grade tumors located in the anterior lobe and/or apex of very large prostate glands. It was not until 2013 that Crawford and our group demonstrated a high clinical-pathology correlation and high accuracy on transperineal mapping biopsies (TPMB) using a 5-mm grid template for the detection of clinically significant PCa. With the aid of special software applications, the pathology results of TPMB were applied to 3 dimensional (3D) reconstructions of in vivo US prostate images, and these results were compared with 3D reconstructions of whole mount radical prostatectomy specimens. Our initial study showed that TPMB provides physicians and patients with a reliable assessment of grade and stage of disease and the opportunity to choose the most appropriate therapeutic options, including targeted focal therapy. This was followed by studies in which we demonstrated that biopsy density (ratio of total number of biopsies to prostate volume) greater than 1.5 increased the diagnosis of prostate cancer by 1.5 times, detects higher Gleason scores and should be considered the optimal sampling approach in selected patients (2019). Thus, TPMB and the use of 3D reconstruction of in vivo prostates closely reflects true PCa disease as found at prostatectomy, it can detect or rule out more aggressive disease, identifying with more accuracy the Gleason grade and tumor size of PCa lesions, ensuring that patients are not mistakenly undertreated or unnecessarily overtreated, minimizing therapy-related morbidity.