Disease resistance is essential for reliable maize production. In a long-term tug-of-war between maize and its pathogenic microbes, naturally occurring resistance genes gradually accumulate and play a key role in protecting maize from various destructive diseases. Recently, significant progress has been made in deciphering the genetic basis of disease resistance in maize. Enhancing disease resistance can now be explored at the molecular level, from marker-assisted selection to genomic selection, transgenesis technique, and genome editing. In view of the continuing accumulation of cloned resistance genes and in-depth understanding of their resistance mechanisms, coupled with rapid progress of biotechnology, it is expected that the large-scale commercial application of molecular breeding of resistant maize varieties will soon become a reality.