The Caribbean and Central America represent a formidable challenge for researchers and policy makers in the HIV field, due to their pronounced heterogeneity in terms of social, economic, and cultural contexts and the different courses the HIV epidemic has followed in the region. Such contrasting contexts and epidemics can be exemplified by 2 countries that share the island of Hispaniola, the French Creole-speaking Haiti, and the Spanish-speaking Dominican Republic. Haiti has experienced the worst epidemics outside of sub-Saharan Africa. Following a protracted economic and social crisis, recently aggravated by a devastating earthquake, the local HIV epidemic could experience resurgence. The region, strategically located on the way between coca-producing countries and the profitable North American markets, has been a transshipment area for years. Notwithstanding, the impact of such routes on local drug scenes has been very heterogeneous and dynamic, depending on a combination of local mores, drug enforcement activities, and the broad social and political context. Injecting drug use remains rare in the region, but local drug scenes are dynamic under the influence of increasing mobility of people and goods to and from North and South America, growing tourism and commerce, and prostitution. The multiple impacts of the recent economic and social crisis, as well as the influence of drug-trafficking routes across the Caribbean and other Latin American countries require a sustained effort to track changes in the HIV risk environment to inform sound drug policies and initiatives to minimize drug-related harms in the region.