Wheat is a crop of historical significance, as it marks the turning point of human civilization 10,000 years ago with its domestication. Due to the rapid increase in population, wheat production needs to be increased by 50% by 2050 and this growth will be mainly based on yield increases, as there is strong competition for scarce productive arable land from other sectors. This increasing demand can be further achieved using sustainable approaches including integrated disease pest management, adaption to warmer climates, less use of water resources and increased frequency of abiotic stress tolerances. Out of 200 diseases of wheat, 50 cause economic losses and are widely distributed. Each year, about 20% of wheat is lost due to diseases. Some major wheat diseases are rusts, smut, tan spot, spot blotch, fusarium head blight, common root rot, septoria blotch, powdery mildew, blast, and several viral, nematode, and bacterial diseases. These diseases badly impact the yield and cause mortality of the plants. This review focuses on important diseases of the wheat present in the United States, with comprehensive information of causal organism, economic damage, symptoms and host range, favorable conditions, and disease management strategies. Furthermore, major genetic and breeding efforts to control and manage these diseases are discussed. A detailed description of all the QTLs, genes reported and cloned for these diseases are provided in this review. This study will be of utmost importance to wheat breeding programs throughout the world to breed for resistance under changing environmental conditions.