Agriculture production is a major driver of destabilization of the earth's planetary boundaries within which humanity can safely operate. Producing enough food that is safe and nutritious is the biggest challenge in 21st century agriculture. Yield gains through genetic enhancement have either slowed down or not rising to the level needed to meet the ever-growing demand for nutritious food. A continuous supply of high-quality crop germplasm is the key to developing climate-resilient, resource-use efficient, nutritious and productive cultivars. Global efforts are underway to develop pre-breeding populations, by exploiting exotic germplasm including wild and weedy relatives with required characteristics to support breeding programs. Comprehensive profiling of germplasm/breeding lines (relative to uncharacterized lines) and adopting a strategy based on physiological characterization of parental lines have the potential to facilitate the accumulation of favorable alleles to enhance genetic gain in plant breeding. Advances in genomics, phenomics and bioinformatic resources have led to the deployment of several knowledge-intensive approaches to accelerate genetic gains in diverse food crops. Enhanced capability in data storage, retrieval and analysis has greatly facilitated the development of genotype-phenotype models to predict phenotypes, thus enhancing selection efficiency. Genomic-aided breeding has been successful in enhancing genetic gain relative to pedigree-based phenotypic selection. Genes controlling “recombination hotspots” and targeted recombination may provide breeders opportunity to significantly increase genetic gains. Combining genomic selection with doubled haploid technology, speed breeding and high-throughput phenomics with genotype-by-sequencing profiling allows the fast transfer of increased genetic gains per unit time. An open source software system has the potential to increase breeding efficiency through data and code sharing, while open source seed systems should allow for continued seed saving, breeding, and seed exchange without restriction. Taken together, these approaches should provide breeders with the opportunity to make genetic gains through new technologies and through the infusion of useful genetic variation in crop breeding.