Lethal phases of the hybrids between Drosophila melanogaster and its sibling species, D. simulans are classified into three types: (1) embryonic lethality in hybrids carrying D. simulans cytoplasm and D. melanogaster X chromosome, (2) larval lethality in hybrids not carrying D. simulans X, and (3) temperature-sensitive pupal lethality in hybrids carrying D. simulans X. The same lethal phases are also observed when either of the two other sibling species, D. mauritiana or D. sechellia, is employed for hybridization with D. melanogaster. Here, we describe genetic analyses of each hybrid lethality, and demonstrate that these three types of lethality are independent phenomena. We then propose two models to interpret the mechanisms of each hybrid lethality. The first model is a modification of the conventional X/autosome imbalance hypothesis assuming a lethal gene and a suppressor gene are involved in the larval lethality, while the second model is for embryonic lethality assuming an interaction between a maternal-effect lethal gene and a suppressor gene.