Bitter taste receptors (TAS2Rs) enable animals to detect and avoid toxins in the environment, including noxious defense compounds produced by plants. This suggests that TAS2Rs are under complex pressures from natural selection. To investigate these pressures, we examined signatures of selection in the primate TAS2R38 gene. Whole-gene (1,002 bp) sequences from 40 species representing all major primate taxa uncovered extensive variation. Nucleotide substitutions occurred at 448 positions, resulting in 201 amino acid changes. Two single-nucleotide deletions, one three-nucleotide in-frame deletion, and one premature stop codon were also observed. The rate of non-synonymous substitution (ω = dN/dS), was high in TAS2R38 (ω = 0.60) compared to other genes, but significantly lower than expected under neutrality (P = 4.0 × 10(-9)), indicating that purifying selection has maintained the basic structure of the receptor. However, differences were present among receptor subregions. Non-synonymous rates were significantly lower than expected in transmembrane domains (ω = 0.55, P = 1.18 × 10(-12)) and internal loops (ω = 0.51, P = 7.04 × 10(-5)), but not external loops (ω = 1.16, P = 0.53), and evidence of positive selection was found in external loop 2, which exhibited a high rate (ω = 2.53) consistent with rapid shifts in ligand targeting. These patterns point to a history of rapid yet constrained change in bitter taste responses in the course of primate evolution.