Apex predators have experienced catastrophic declines throughout the world as a result of human persecution and habitat loss. These collapses in top predator populations are commonly associated with dramatic increases in the abundance of smaller predators. Known as “mesopredator release,” this trophic interaction has been recorded across a range of communities and ecosystems. Mesopredator outbreaks often lead to declining prey populations, sometimes destabilizing communities and driving local extinctions. We present an overview of mesopredator release and illustrate how its underlying concepts can be used to improve predator management in an increasingly fragmented world. We also examine shifts in North American carnivore ranges during the past 200 years and show that 60% of mesopredator ranges have expanded, whereas all apex predator ranges have contracted. The need to understand how best to predict and manage mesopredator release is urgent—mesopredator outbreaks are causing high ecological, economic, and social costs around the world.