The patterns of postmating reproductive isolation in general follow Haldane's rule that the heterogametic sex is much more likely to become inviable or sterile than the homogametic sex. There are two approaches to explaining the rule. The first approach assumes that genic divergence affects both sexes equally but their difference in chromosome constitution leads to the sex:dependent manifestation; for example, the heterogametic hybrids have a greater degree of X-autosome imbalance. The second approach assumes that genes affecting the heterogametic sex have evolved more rapidly and the genotypic difference between sexes is unimportant. Neither approach in its search for a unitary genetic basis of Haldane's rule has been successful. The major point of this article is that Haldane's rule is most likely a composite rule--the first approach is appropriate for hybrid inviability but is not sufficient for hybrid sterility, which requires the second approach in addition. Three lines of evidence are presented: (1) genes causing hybrid inviability generally do not behave in a sex-dependent manner and, thus, X-autosome imbalance is crucial; (2) interspecific crosses yielding sterility outnumber those yielding inviability by more than 10-fold in Drosophila and mammals; and (3) in Drosophila, genes causing hybrid male sterility greatly outnumber genes causing male inviability. Several models pertaining to the faster evolution of hybrid sterility in the heterogametic sex (than in the homogametic sex) are discussed. Finally, genes affecting the viability and fertility of interspecific hybrids seem to belong in a class distinct from those represented in mutagenic studies or those detected as intraspecific variations. The implications of this qualitative and quantitative break at the species level need to be heeded.