Meiotic drive loci distort the normally equal segregation of alleles, which benefits their own transmission even in the face of severe fitness costs to their host organism. However, relatively little is known about the molecular identity of meiotic drivers, their strategies of action, and mechanisms that can suppress their activity. Here, we present data from the fruitflyDrosophila simulansthat address these questions. We show that a family of de novo, protamine-derived X-linked selfish genes (theDoxgene family) is silenced by a pair of newly emerged hairpin RNA (hpRNA) small interfering RNA (siRNA)-class loci,NmyandTmy. In thew[XD1]genetic background, knockout ofnmyderepressesDoxandMDoxin testes and depletes male progeny, whereas knockout oftmycauses misexpression ofPDoxgenes and renders males sterile. Importantly, genetic interactions betweennmyandtmymutant alleles reveal thatTmyalso specifically maintains male progeny for normal sex ratio. We show theDoxloci are functionally polymorphic withinD.simulans, such that bothnmy-associated sex ratio bias andtmy-associated sterility can be rescued by wild-type X chromosomes bearing natural deletions in differentDoxfamily genes. Finally, using tagged transgenes ofDoxandPDox2, we provide the first experimental evidence Dox family genes encode proteins that are strongly derepressed in cognate hpRNA mutants. Altogether, these studies support a model in which protamine-derived drivers and hpRNA suppressors drive repeated cycles of sex chromosome conflict and resolution that shape genome evolution and the genetic control of male gametogenesis.