Soybean yields worldwide are reduced by a variety of diseases. Advances in breeding techniques have facilitated the development of soybean cultivars with broader and more durable resistance, but continued reliance on a small number of major resistance genes remains a concern. Introgression of resistance genes from unadapted germplasm sources with a reduced risk of linkage drag has become more efficient with marker-assisted selection. Advances in DNA sequencing and other technologies have made it possible to identify novel resistance loci and candidate genes. This chapter summarizes what is currently known about resistance to some of the major diseases affecting soybean production, particularly in North America, and genes that condition resistance to those diseases.