Focal ablative therapy may be reasonable for some patients with prostate cancer; selection factors include a variety of clinical and pathologic factors in combination with informed patient choice. Our group evaluated 4 specific pathologic features that may influence this treatment decision. We reviewed the published literature for applicable studies regarding the natural history of prostate cancer, multifocality, cancer volume, and accuracy of cancer detection by current methods. Results were as follows: (1)Latent versus incidental cancer: Is there any utility in separating latent cancer (autopsy- or cystoprostatectomy-detected incidental cancer) from nonlatent cancer (clinically detected cancer)? Prostate cancer is biologically and morphologically heterogeneous, including its malignant potential. We conclude that the ability to detect the biologic potential of prostate cancer in the individual patient is imperfect on the basis of currently available clinical and pathologic data. The best evidence indicates that latent cancer is a medical misnomer, so this separation has no biologic or clinically useful value. We recommend that the term “latent” cancer be abandoned. (2)Multifocality: About 80% of incidental cancers measure <0.5 mL in volume and are assigned a Gleason score of ≤6, indicating low malignant potential. Such microscopic foci do not influence serum prostate-specific antigen (PSA) concentration and likely have minimal effect on survival. However, a small but significant number of microscopic cancers are assigned higher Gleason scores and pose a risk for the patient; 16% of such foci consist of primary Gleason grade 4 cancer. (3)Cancer volume: Cancer volume within the prostate predicts the extent of cancer at autopsy with a reasonable degree of accuracy: 10% risk for extraprostatic extension with 0.5-cm3 cancer; 10% risk for seminal vesicle invasion with 4-cm3 cancer; and 10% risk for lymph node metastases with 5-cm3 cancer. Cancer volume is an important defining factor for both definitions of “clinically insignificant” cancer: (a) cancer <0.5-cm3, Gleason score 7, and organ confined; (b) cancer that will not reach a volume of 20 cm3 by the time of expected death according to patient age, estimated life expectancy, and cancer volume at diagnosis. The volume of cancer in lymph node metastasis is an important predictor of progression in prostate cancer. When systemic progression was predicted with use of the Cox multivariate analysis, only nodal cancer volume added significantly to the model that contained the primary cancer variables (Gleason score, cancer volume, and DNA ploidy). The relative hazard rate for a doubling in nodal cancer volume was 1.6 (95% confidence interval, 1.3 to 2.0; P <0.0001). (4)Cancer detection methods: Multiple factors determine the yield of prostate cancer by biopsy, including uncontrollable patient- and prostate-related risk factors (eg, serum PSA, prostate volume) and factors controllable by the urologist (eg, number of biopsies obtained) or the pathologist (eg, number of tissue slices obtained, expertise of the histotechnologist). It is concluded that multiple pathologic factors influence the choice of focal prostate cancer therapy for select patients, including multifocality, cancer volume, and cancer detection methods.