We analyzed uncertainties and complexities of the Zika virus outbreak in Brazil, and we discuss risk reduction for future emergencies. We present the public health situation in Brazil and concurrent determinants of the epidemic and the knowledge gaps that persist despite building evidence from research, making public health decisions difficult. Brazil has adopted active measures, but producing desired outcomes may be uncertain because of partial or unavailable information. Reducing population group vulnerabilities and acting on environmental issues are medium- to long-term measures. Simultaneously dealing with information gaps, uncontrolled disease spread, and vulnerabilities is a new risk scenario and must be approached decisively to face emerging biothreats.