Lycopene has been proposed to protect against prostate cancer through various properties including decreased lipid oxidation, inhibition of cancer cell proliferation, and most notably potent antioxidant properties. Epidemiologic studies on the association between lycopene and prostate cancer incidence have yielded mixed results. Detection of an association has been complicated by unique epidemiologic considerations including the measurement of lycopene and its major source in the diet, tomato products, and assessment of prostate cancer incidence and progression. Understanding this association has been further challenging in the prostate-specific antigen (PSA) screening era. PSA screening has increased the detection of prostate cancer, including a variety of relatively indolent cancers. This paper examines the lycopene and prostate cancer association in light of epidemiologic methodologic issues with particular emphasis on the effect of PSA screening on this association.