The call to set aside half of Earth's surface for nature conservation is gaining momentum across the conservation community. We propose that the experiences of Earth's most extensive conservation network, Natura 2000, offers important lessons on the challenges and opportunities of scaling up area-based conservation strategies. Natura 2000 has made unprecedented advances in implementing effective, evidence-based, internationally collaborative conservation policies and practices at continental scales. These advances have relied on strong governance frameworks, standardized policies, close integration of science and policy, flexibility in protection designations, a focus on conservation outside protected areas, economic interests and development, and the engagement and incentivization of stakeholders at different scales of reserve development and operation. Although failures and gaps remain, these hard-won lessons of Natura 2000 have much to offer those aiming to scale up conservation globally to meet the biodiversity challenges of the Anthropocene.