African economies historically have been associated with natural resources and raw materials. But contrary to this dominant image, African countries still suffer from chronic food shortages and recurrent famines. Such episodes often have been treated as ephemeral, requiring short-term responses through food aid. However, their intensity and frequency have been rising, suggesting the existence of major challenges to the sustainability transition. These challenges also present major opportunities. First, there is growing recognition that promoting African agricultural sustainability must be tackled in the wider context of economic modernization programs and not simply through local interventions. Secondly, such modernization will require considerable investment in the continent’s capacity to utilize and generate new scientific and technical knowledge. This paper focuses on the dual task of defining agriculture as a central theme in the wider context of economic transformation and the specific role that science and innovation can play in that process. More fundamentally, the paper stresses the importance of framing agricultural sustainability in the context of “innovation systems” and rejects the classical view of considering agriculture as a separate sector requiring unique policy interventions that are decoupled from the wider process of economic learning. This is not to deny the centrality of agriculture in African economies. To the contrary, it argues that agriculture, as a central locus for economic learning, requires the intensive use of new technical knowledge. This view has far-reaching implications for the structure and functioning of African governments as well as the nature of international development partnerships.