The Segregation Distorter (SD) complex in the centromeric region of chromosome 2 in Drosophila melanogaster is responsible for a naturally occurring and strong system of male meiotic drive. Earlier recombinational dissection and deletional analysis showed that the SD complex resolves into three major loci: the euchromatic Sd, or Segregation distorter gene at the base of the left arm of the chromosome (2L), and two heterochromatic genes: E(SD), the Enhancer of SD, and Rsp, the Responder, in the center of the left arm and the right arm (2R), respectively. Rsp exists in the major allelic forms, RsPs, for sensitive, and Rspi, for insensitive. Males that are heterozygous for an SD chromosome (SdE(SD)Rspi) and a sensitive SD+ homologue (Sd+E(SD)+Rsps) transmit predominantly or even exclusively the SD-bearing chromosome to the progeny. The distortion of the segregation ratio is traceable to failure in chromatin condensation and maturation of those spermatids that receive the Rsps homologue during meiosis. Characterization of the properties of null alleles of Sd, E(SD), and Rsp that were generated by deletion determined the precise cytological locations of the components and established the functional relationship of each to its wild-type counterpart, suggesting a model whereby a deleterious action of Sd, along with E(SD), on the Rsps target sets in motion the events culminating in sperm dysfunction. Further genetic analysis of E(SD), a gene required for full expression of drive, showed that E(SD) in two doses can cause significant distortion even in the absence of Sd. This distortion is suppressible by a suppressor of SD action. Thus, E(SD) is more than a simple modifier of Sd; rather, it is an effector locus that, like Sd, can act at the Rsps target. Cloning and molecular analysis of the Sd locus reveal that the alteration uniquely associated with Sd is a 5-kb tandem duplication within the polytene band 37D5, which is where Sd is known to map. The Sd-associated duplication appears to be part of a large gene about 100 kb in size. A 4.2-kb SD-specific transcript has been identified, and analyses of the cDNAs indicate a complex transcription pattern. Since Responder plays such a key role in segregation distortion, recent progress in analyzing this locus has been exciting. Studies of Rsp at the genetic, cytogenetic, and molecular levels have been mutually reinforcing and consistent in demonstrating that Rsp is an extended locus that is (1) subdivisible and (2) associated with a 120-bp repeated sequence of DNA that is rich in adenine-thymine pairs and whose copy number is correlated with the degree of sensitivity. In an exceptional situation, there are certain SdRspi/Sd+ Rsps males cartying particular modifiers in which the Rspi chromosome can he transmitted at frequencies of less than 0.50 relative to the Rsps chromosome, suggesting that the genetics of segregation ratios may involve even further complexities, which need to be unraveled.