The Rio de la Plata region (Argentina, Uruguay, and southern Brazil) is currently characterized by a mosaic of intensively managed croplands and remaining areas of livestock production on native grasslands. The production of crops and animals in this scenario is usually spatially segregated as a result of mindset and structural constraints developed over decades of agricultural specialization. However, several studies have suggested that crop-livestock integration across various spatio-temporal scales can improve land-use efficiency and ecosystem services provisioning. In this context, the long-standing tradition of Rio de la Plata region‟s ranchers on sheep production summed to the easy-to-manage body size of these small ruminants make them fit into a wide range of farm sizes and integrated crop-livestock system (ICLS) designs. In addition, the large variety of crops produced in the region, including annual (e.g., soybean, maize, rice and wheat) and perennial (e.g., orchards, vineyards and woodlands), and the diversity of temperate and tropical forage species used in livestock systems, provide multiple ICLS possibilities. In this review, we explore these possibilities and highlight the opportunities and challenges for integration of crop and sheep production in the Rio de la Plata region of South America. Using mainly data from the region‟s ICLS, but also other parts of the world, we show that ICLS with sheep are able to improve nutrient cycling, land-use efficiency, and systems‟ resilience and profitability if sound grazing intensities are used. Finally, we build on the idea of ICLS farm design to present an interactive, hands-on methodology recently developed to support farmers‟ transition from specialized systems to ICLS.