The increasing isolation of protected areas poses a serious threat to the long-term viability of many wildlife populations and migrations in Africa. While ecologists have debated the impact of isolation on wildlife populations in reserves, field studies conducted over the past decade now provide a much clearer understanding of the effects. The primary drivers of isolation of protected areas are habitat loss, fences and roads, overhunting, and disease. These drivers restrict the movement of wildlife into and out of reserves and create sinks in the increasingly human-dominated matrix that surrounds most reserves. Post-establishment patterns of extinction of large mammal species in African reserves indicate that area and edge effects are important determinants of species persistence. Interactions and feedbacks between reserve isolation, human-related activities and natural processes within and outside reserves can occur, yet are poorly understood. The problem of reserve isolation must therefore be addressed with a multi-pronged conservation strategy.