Cancers of the prostate contribute substantial morbidity and mortality to the male population. The correlation of prostate cancer incidence with aging suggests that the disease burden associated with prostate carcinoma will increase dramatically over the next several decades. Despite the large number of fatalities directly linked to prostate cancer, most men harboring the disease will die of other causes. This fact poses substantial dilemmas for screening programs designed to diagnose cancers at an early stage, as the optimal approach also would provide guidance as to which cancers could or should be observed, versus those malignancies that require curative therapy, and whether localized treatments are sufficient or if additional systemic interventions are indicated. To address these issues, substantial resources have been focused on the identification of biomarkers capable of specifically and sensitively diagnosing prostate cancers and providing prognostic information. However, the discovery and use of biomarkers must contend with the complexity and heterogeneity of body fluids and tissues. This review describes approaches that use cell type-specific analysis methods to identify cancer-associated features with the potential of distinguishing individuals with cancer of the prostate.