The emergence of Zika virus (ZIKV), in a region confronting the challenge of vector control, showed the risk of sustained ecological and social suitability for the settlement of Aedes sp.-transmitted arboviruses. The lack of proper previous mosquito control, the highly interconnected world by travel, and the difficulty detecting asymptomatic infections, allowed a broad and rapid distribution of ZIKV in Latin America infecting communities with previous exposure to other flaviviruses, and a more diverse population facing aging and co-morbidities. In this scenario, previously unseen atypical and severe cases started to be reported as well as fetal compromise when infection happened during pregnancy. Moreover, co-circulation with other arboviruses, each one with different implications in terms of morbidity, mortality, and chronic burden, and the cross-reactivity with dengue and yellow fever, highlighted the need of adequate diagnostic tools for rapid assessment of etiologic agent in acute febrile patients from tropical areas. And the report of co-infections with other arboviruses and other infectious agents, like bacteria, broaden the clinical spectrum of the disease. Then, a previously considered benign febrile disease turned into the spotlight of scientists. The aim of this conference is to briefly introduce some of the social and ecological aspects that probably facilitated ZIKV spread in the Americas, and to show how comorbidities, co-circulation and co-infections probably helped to modify the disease course leading to the emergence of severe and fatal disease, and to adverse fetal outcomes. A recent systematic review conducted by our group during epidemics found that co-morbidities would be a risk factor for atypical disease. Current efforts in our group are turned to the description of the entire clinical spectrum of ZIKV infection, the importance of differential diagnosis in terms of follow up, the role of previous dengue exposure shaping adaptive immune response and acting as a risk factor for adverse prenatal and postnatal outcomes, and the effect of co-infection in terms of modification of immune response and the clinical severity in patients from an endemic area in Colombia.