A role for serotonin in male sexual preference was recently uncovered by our finding that male mutant mice lacking serotonin have lost sexual preference. Here we show that female mouse mutants lacking either central serotonergic neurons or serotonin prefer female over male genital odors when given a choice, and displayed increased female-female mounting when presented either with a choice of a male and a female target or only with a female target. Pharmacological manipulations and genetic rescue experiments showed that serotonin is required in adults. Behavioral changes caused by deficient serotonergic signaling were not due to changes in plasma concentrations of sex hormones. We demonstrate that a genetic manipulation reverses sexual preference without involving sex hormones. Our results indicate that serotonin controls sexual preference.sexual behaviors | neurotransmitter | Tph2 knockout S exual behaviors are among the most important social behaviors. Although preference for the opposite sex is essential for reproduction, sexual behaviors toward members of the same sex have been observed in many animal species, indicating that there are potential evolutionary advantages (1, 2). The diversity of sexual preference has been of scientific interest to scholars from Aristotle to present-day scientists (2, 3).Biologically, changes in sex hormones can change sexual behavior or sexual preference, resulting in either a loss of sexual preference or a reversal of sexual preference (4-14). Although a genetic component for homosexual orientation has been suggested (15), no specific genes have been identified in sexual preference in humans (16)(17)(18)(19)(20).Same-sex preference was reported in female mice lacking the gene encoding estrogen-binding plasma protein alpha-fetoprotein (AFP) or those lacking the gene for aromatase through indirect effects on sex hormones (11,12,14,21). Pheromone perception is important for sexual behaviors. Surgical removal of the vomeronasal organ or genetic inactivation of transient receptor potential channel 2 (TrpC2), which encodes a cation channel in the vomeronasal organ (22, 23), or cyclic nucleotide-gated channel α2 (Cgna2) in the main olfactory epithelium (24) resulted in loss of sexual preference in male mice. TrpC2 −/− mutant females showed female-female mounting behavior (13, 25). There was an overall reduction of sexual behavior in Cgna2 mutant mice (19). However, none of these mice has been shown to prefer the same sex.Our recent genetic studies have shown that 5-hydroxytryptamine (5-HT) in the male mouse brain is required for sexual preference because there was no sexual preference in mutant male mice lacking serotonergic neurons or 5-HT (26). We have now carried out experiments to determine whether 5-HT is involved in female sexual preference. Here we report a crucial role of serotonergic signaling in female sexual preference: strikingly, sexually differential olfactory preference indicated by several assays was reversed in female mice lacking serotonergic neurons or those unable...