Arboviral diseases comprise a group of important infectious diseases imposing a heavy burden to public health in many locations of the world. Orthoflaviviruses are viruses belonging to the genus Orthoflavivirus; this genus includes some of the most relevant arboviruses to human health. Orthoflaviviruses can infect several different hosts, with some species being transmitted in cycles involving birds and anthropophilic mosquitoes and others transmitted between mammals and mostly Aedes sp. mosquitoes. Some of the most important sylvatic reservoirs of orthoflaviviruses are non-human primates (NHPs). Many flaviviruses that infect NHPs in nature have the potential to cause epidemics in humans, as has been observed in the cases of Orthoflavivirus denguei (dengue virus – DENV), Orthoflavivirus flavi (yellow fever virus – YFV), and Orthoflavivirus zikaense (Zika virus – ZIKV). In this minireview, we discuss important aspects regarding history, ecology involving NHP, distribution, disease outcome, and pathogenesis of these three major orthoflaviviruses that affect humans and NHP and relate this information to the potential of using NHP as experimental models. In addition, we suggest some orthoflaviviruses that could be better investigated, both in nature and in experimental studies, in light of the recent revolution in molecular biology.