This chapter critically examines early sixteenth-century Spanish slave-raiding and invasion-related violence in the Caribbean and Mesoamerica, emphasising the varied ways whereby indigenous peoples sought to mitigate, incorporate or reject the newcomers’ presence in the region. It begins with Columbus’s 1492 voyage and subsequent Spanish slaving activities in the Caribbean, then turns to the Spanish–Aztec War that devastated central Mexico, before closing with a discussion of the ‘Thirty Years War’ that disrupted Maya kingdoms. By connecting disparate flashpoints of war, high mortality rates, the enslavement of indigenous peoples and internal displacement, the long and complex tradition of violence that underpinned Spanish efforts to subjugate Aztecs, Mayas and hundreds of thousands of other indigenous peoples will be explored. Patterns to violence and warfare, however, were not unilateral; the leaders of indigenous Caribbean and Mesoamerica polities utilised violence according to their own customs and agendas. These particular wars of invasion and conquest can therefore be understood as part of a larger, multifaceted process.