The recent rapid emergence of maize lethal necrosis (MLN), caused by coinfection of maize with Maize chlorotic mottle virus (MCMV) and a second virus usually from the family Potyviridae, is causing extensive losses for farmers in East Africa, Southeast Asia, and South America. Although the genetic basis of resistance to potyviruses is well understood in maize, little was known about resistance to MCMV. The responses of five maize inbred lines (KS23-5, KS23-6, N211, DR, and Oh1VI) to inoculation with MCMV, Sugarcane mosaic virus, and MLN were characterized. All five lines developed fewer symptoms than susceptible controls after inoculation with MCMV; however, the virus was detected in systemic leaf tissue from each of the lines similarly to susceptible controls, indicating that the lines were tolerant of MCMV rather than resistant to it. Except for KS23-5, the inbred lines also developed fewer symptoms after inoculation with MLN than susceptible controls. To identify genetic loci associated with MCMV tolerance, large F2 or recombinant inbred populations were evaluated for their phenotypic responses to MCMV, and the most resistant and susceptible plants were genotyped by sequencing. One to four quantitative trait loci (QTL) were identified in each tolerant population using recombination frequency and positional mapping strategies. In contrast to previous studies of virus resistance in maize, the chromosomal positions and genetic character of the QTL were unique to each population. The results suggest that different, genotype-specific mechanisms are associated with MCMV tolerance in maize. These results will allow for the development of markers for marker-assisted selection of MCMV- and MLN-tolerant maize hybrids for disease control.