Crop losses from pests threaten global food security and safety. In the last six decades, pest control using chemical pesticides has resulted in important yield gains per unit area, worldwide. However, the long-term sustainability of chemical pest control has been increasingly thrown into doubt due to the negative impact on human health, biodiversity, and the environment. Consequently, there is an urgent need to improve the science of crop protection in order to tackle the five key challenges of 21st century agriculture holistically: (i) maintaining or improving agricultural productivity, (ii) producing healthy food, (iii) reducing the negative impacts of agriculture on ecosystem and human health, (iv) ensuring the economic viability of farms, and (v) adapting agriculture to climate change. Agroecological Crop Protection (ACP) can be a powerful approach to address these challenges, as we demonstrate in this paper. ACP is the application of the principles of agroecology to crop protection in order to promote virtuous and sustainable changes in agriculture and food systems. ACP combines multiple approaches and disciplines including ecology, agroecology, and Integrated Pest Management. It promotes a crop protection system compatible with healthy agricultural and food systems, agroecological principles and the “one health” approach. We predict that ACP will meet the challenge of pesticide-free agriculture in the future. In this paper, we will first present the scientific, agricultural and social components of ACP. We will then analyze the research approaches, questions, methods and tools needed to adopt ACP. Finally, we suggest key mechanisms to facilitate the transition to ACP, which will ultimately provide sustainable food, feed, and fuel in a context of major global change.