Wheat breeders have delivered high yield, high quality varieties that currently underpin global food security. However, a new challenge lies ahead to improve sustainability of crop production. While genetic gain must further increase to meet the demand of 10 billion people by 2050, climate change and rapidly evolving diseases are set to impact global wheat production and supply. In parallel, there is growing pressure to reduce the environmental footprint of agricultural systems, including management of water at the ecosystem level and reducing emissions and inputs on farms, such as diesel, fertilizer, herbicide and fungicide. The Green Revolution boosted farm productivity through enhanced genetics and management practices that rely on moderate to high inputs. Thus, a big challenge ahead for wheat breeders is developing high yielding varieties that offer enhanced sustainability. The adoption of optimal genotype by management (G × M) packages could help improve efficiencies and close the yield gap. However, management practices are traditionally optimized independent of the breeding process. Selection for performance under new management practices, or the interactive traits, early in the breeding cycle could help close the yield gap in a range of environments. New artificial intelligence (AI)-guided breeding methodologies can support the rapid stacking of traits, including nutrient and water-use efficiency traits. However, the trait × trait × environment interactions are highly complex and requires modelling to define breeding targets. There are also opportunities to improve sustainability post-farmgate. For instance, future varieties could be bred for more efficient food processing or higher feed efficiency for feedlots. Wheat breeders are well-placed to rise to these challenges with an impressive toolkit of breeding technologies, which will play an important role to accelerate modern breeding programs and deliver new varieties with improved sustainability and profitability across the value-chain.