Hybrid incompatibilities play a critical role in the evolution and maintenance of species. We have discovered a simple genetic incompatibility that causes lethality in hybrids between two closely related species of yellow monkeyflower (Mimulus guttatus and M. nasutus). This hybrid incompatibility, which causes one sixteenth of F2 hybrid seedlings to lack chlorophyll and die shortly after germination, occurs between sympatric populations that are connected by ongoing interspecific gene flow. Using complimentary genetic mapping and gene expression analyses, we show that lethality occurs in hybrids that lack a functional copy of the critical photosynthetic gene pTAC14. In M. guttatus, this gene was duplicated, but the ancestral copy is no longer expressed. In M. nasutus, the duplication is missing altogether. As a result, hybrids die when they are homozygous for the nonfunctional M. guttatus copy and missing the duplicate from M. nasutus, apparently due to misregulated transcription of key photosynthetic genes. Our study indicates that neutral evolutionary processes may play an important role in the evolution of hybrid incompatibilities and opens the door to direct investigations of their contribution to reproductive isolation among naturally hybridizing species.