It is widely appreciated that neurotransmission systems interact in their effects on human cognition, but those interactions have been little studied. We used genetics to investigate pharmacological evidence of synergisms in nicotinic/muscarinic interactions on cognition. We hypothesized that joint influences of nicotinic and muscarinic systems would be reflected in cognitive effects of normal variation in known SNPs in nicotinic (CHRNA4 rs1044396) and muscarinic (CHRM2 rs8191992) receptor genes. Exp. 1 used a task of cued visual search. The slope of the cue size/reaction time function showed a trend level effect of the muscarinic CHRM2 SNP, no effect of the nicotinic CHRNA4 SNP, but a significant interaction between the 2 SNPs. Slopes were steepest in individuals who were both CHRNA4 C/C and CHRM2 T/T homozygotes. To determine the specificity of this synergism, Exp. 2 assessed working memory for 1-3 locations over 3 s and found no significant effects on either SNP. Interpreting these results in light of Sarter's [Briand LA, et al. (2007) Modulators in concert for cognition: Modulator interactions in the prefrontal cortex. Prog Neurobiol 83:69-91] claims of tonic and phasic modes of cholinergic activity, we argue that reorienting attention to the target after invalid cues requires a phasic response, dependent on the nicotinic system, whereas orienting attention to valid cues requires a tonic response, dependent on the muscarinic system. Consistent with that, shifting and scaling after valid cues (tonic) were strongest in CHRNA4 C/C homozygotes who were also CHRM2 T/T homozygotes. This shows synergistic effects within the human cholinergic system.