Crossbreeding, considering either terminal or rotational crossing, synthetic breed creation or breed replacement, is often promoted as an efficient strategy to increase farmers’ income through the improvement of productivity of local livestock in developing countries. Sustainability of crossbreeding is however frequently challenged by constraints such as poor adaptation to the local environment or lack of logistic support. In this review, we investigate factors that may influence the long-term success or the failure of crossbreeding programs, based on the scientific literature and country reports submitted for The Second Report on the State of the World’s Animal Genetic Resources for Food and Agriculture. Crossbreeding activities vary widely across species and countries. Its sustainability is dependent on different prerequisites such as continual access to adequate breeding stock (especially after the end of externally funded crossbreeding projects), the opportunity of improved livestock to express their genetic potential (e.g. through providing proper inputs) and integration within a reliable market chain. As formal crossbreeding programs are often associated with adoption of other technologies, they can be a catalyst for innovation and development for smallholders. Given the increasing global demand for animal products, as well as the potential environmental consequences of climate change, there is a need for practical research to improve the implementation of long-term crossbreeding programs in developing countries.