Desmoplastic melanoma (DM) is an uncommon variant of melanoma that can be challenging to diagnose. Phenotypic variations in terms of the proportion of spindled cells and fibromucinous stroma have led to the subclassification of pure (>90% spindled cells) and mixed (<90% spindled cells admixed with epithelioid cells) histopathologic DM subtypes. This subclassification is not just semantic; several studies have underscored differences in clinical and prognostic behaviors of the subtypes. In this review, we parse the literature on DM subtypes with an emphasis on histopathologic, immunohistochemical, and genetic data to ascertain whether these factors influence and/or affect their differing biological behaviors. Demographics regarding age, location, and clinical behavior of the subtypes are detailed, as is the impact of dermoscopy as a diagnostic adjunct. Despite the plethora of markers used, our findings suggest that few differentiate between the DM subtypes. Differential expression of PD-L1 suggests that patients with the mixed subtype are likely better candidates for anti-PD/PD-L1 therapy. Significant differences between the subtypes in terms of neurofibromin expression and the frequency of TERT promoter mutations suggest that the subtypes have distinct genetic drivers. Thus, immunohistochemical and genetic analyses imply that these likely affect the biological behaviors of the DM subtypes.