As the coronavirus disease 2019 (COVID- 19) continues to spread worldwide, it has become evident that the morbidity and mortality rates clearly vary across nations. Although several factors may account for this disparity, striking differences within and between populations indicate that ethnicity might impact COVID-19 clinical outcomes, reflecting the 'color of disease'. Therefore, the role of key biological variables that could interplay with viral spreading and severity indices has attracted increasing attention, particularly among non-C aucasian populations. Although the links between vitamin D status and the incidence and severity of COVID-19 remain elusive, several lines of emerging evidence suggest that vitamin D signaling, targeting several immune-mediated pathways, may offer potential benefits at different stages of SARS-CoV-2 infection. Given that the vitamin D status is modulated by several intrinsic and extrinsic factors, including skin type (pigmentation), melanin polymers may also play a role in variable COVID- 19 outcomes among diverse population settings. Moreover, apart from the well-known limiting effects of melanin on the endogenous production of vitamin D, the potential crosstalk between the pigmentary and immune system may also require special attention concerning the current pandemic. The present review article aimed to shed light on a range of mostly overlooked host factors, such as vitamin D status and melanin pigments, that may influence the course and outcome of COVID- 19. © This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) License.