Prostate cancer management has traditionally relied upon risk stratification of patients based on Gleason score, pretreatment prostate-specific antigen and clinical tumor stage. However, these factors alone do not adequately reflect the inherent complexity and heterogeneity of prostate cancer. Accurate and individualized risk stratification at the time of diagnosis is instrumental to facilitate clinical decision-making and treatment selection tailored to each patient. The incorporation of tissue and genetic biomarkers into current prostate cancer prediction models may optimize decision-making and improve patient outcomes. In this review we discuss the clinical significance of unfavorable morphologic features such as cribriform architecture and intraductal carcinoma of the prostate, tissue biomarkers and genomic tests and assess their potential use in prostate cancer risk assessment and treatment selection.