Focal therapy is emerging as a potential challenge to the standard of care for localized prostate cancer. Short-term quality-of-life outcomes such as genitourinary side effects, anxiety levels, and global measures of quality of life using validated questionnaires are vital although proof-of-concept trials and retrospective case series have already established lower toxicity from focal therapy in some detail. Defining what outcomes will be measured and what defines a successful focal treatment in the medium and long term is problematic. Measuring long-term efficacy or effectiveness within a randomized trial is somewhat straightforward since hard endpoints are measured such as presence or absence of metastatic disease and/or death. However, owing to the long natural history of localized prostate cancer detected in the modern prostate-specific antigen screening era, with these events usually occurring a minimum of 10 years after therapy makes such a long-term trial large, costly, and probably unfeasible now. This article discusses the optimal determinants of success or failure for focal therapy that require careful consideration within multicenter trials evaluating medium-term oncological efficacy.