Melanoma's incidence and mortality for certain groups has appeared to level off after a steady increase over the last half century. This trend is suspected to be due to better detection and removal of thin, biological early melanomas. However, to date, no prospective evidence exists to clearly demonstrate the efficacy of prevention and early detection in decreasing melanoma mortlity. Nonetheless, many studies suggest that both self-assessment of risk factors or clinician examination can identify a proportion of patients at highest risk for melanoma who may benefit from behavior modification (primary prevention) and routine screening (secondary prevention). Compromising these goals is the fact that neither the clinical or histologic diagnosis of melanoma is 100% accurate. Clinical diagnosis of melanoma, based on evaluation of a skin lesion's color and shape, correlates best with the experience of the clinician. Ancillary technologies have been developed to improve clinical accuracy of suspicious skin lesions but a subset of melanomas exist that do not fall in the spectrum of the 'ABCDE' guidelines commonly used for melanoma identification. Similarly, at the histologic level (the 'gold standard' of diagnosis), overlap exists between benign and malignant melanocytic proliferations leading to both over and underdiagnosis of melanoma. A better understanding of melanoma's pathogenesis has identified disease-related biomarkers that may more reliably differentiate a melanocytic nevus from melanoma. In this paper, we review current and novel, potentially more accurate, biomarkers and supplementary technologies that can be used for the prevention, screening and diagnosis of melanoma.