Distinction between normal skin and pathology can be a diagnostic challenge. This systematic review summarizes how various contrast agents, either topically delivered or injected into the skin, affect distinction between skin disease and normal skin when imaged by optical coherence tomography (OCT) and confocal microscopy (CM). A systematic review of in vivo OCT and CM studies using exogenous contrast agents on healthy human skin or skin disease was performed. In total, nine CM studies and one OCT study were eligible. Four contrast agents aluminum chloride (AlCl) n = 2, indocyanine green (ICG) n = 3, sodium fluorescein n = 3 and acetic acid n = 1 applied to CM in variety of skin diseases. ICG, acetic acid and AlCl showed promise to increase contrast of tumor nests in keratinocyte carcinomas. Fluorescein and ICG enhanced contrast of keratinocytes and adnexal structures. In OCT of healthy skin gold nanoshells, increased contrast of natural skin openings. Contrast agents may improve delineation and diagnosis of skin cancers; ICG, acetic acid and AlCl have potential in CM and gold nanoshells facilitate visualization of adnexal skin structures in OCT. However, as utility of bedside optical imaging increases, further studies with robust methodological quality are necessary to implement contrast agents into routine dermatological practice.