Treatment of prostate cancer using high-intensity focused ultrasound (HIFU) focal therapy will become a reliable treatment option only if several conditions are fulfilled. These conditions concern patient selection, assessment of the tumour location and aggressiveness, evaluation of target tissue destruction, and detection of local recurrence or appearance of new tumours. Regarding patient selection, standard transrectal biopsies are not accurate enough and, although perineal template biopsies can detect tumours, they are invasive, expensive procedures, and there is a risk of incidental detection of insignificant cancers. In turn, multiparametric MRI is accurate for detecting and localizing high-grade (Gleason score ≥7) cancers and may provide non-invasive assessment of tumour aggressiveness. Moreover, contrast-enhanced imaging-ultrasonography or MRI-can assess post-HIFU tissue destruction and provide accurate detection of tumour recurrence, which is a key element for follow up. This Perspectives article will assess whether our current methods for cancer diagnosis, tissue targeting, and treatment follow up are accurate enough to allow the design of robust HIFU focal therapy protocols.