Genetic analysis of nuclear-cytoplasm incompatibilities is not straightforward and requires an elaborated experimental design. A number of species have been genetically studied, but notable advances in genetic mapping of nuclear loci involved in nuclear-plastid incompatibility have been achieved only in wheat and pea. This review focuses on the study of the genetic background underlying nuclear-plastid incompatibilities, including cases where the molecular genetic basis of such incompatibility has been unveiled, such as in tobacco, Oenothera, pea, and wheat.