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Melanoma is the deadliest form of skin cancer and remains a diagnostic challenge in the dermatology clinic. Several non-invasive imaging techniques have been developed to identify melanoma. The signal source in each of these modalities is based on the alteration of physical characteristics of the tissue from healthy/benign to melanoma. However, as these characteristics are not always sufficiently specific, the current imaging techniques are not adequate for use in the clinical setting. A more robust way of melanoma diagnosis is to “stain” or selectively target the suspect tissue with a melanoma biomarker attached to a contrast enhancer of one imaging modality. Here, we categorize and review known melanoma diagnostic biomarkers with the goal of guiding skin imaging experts to design an appropriate diagnostic tool for differentiating between melanoma and benign lesions with a high specificity and sensitivity.