Our understanding of the evolution of organismal diversity is restricted by the current resolution of the genotype-phenotype map. In particular, the genetic basis of environmentally relevant phenotypic variation among natural populations remains poorly understood. Trichomes are single-cell outgrowths on the surface of plant leaves and other above-ground organs. Consistent with trichomes" suggested function to protect plants from predators and abiotic stressors [1-3], trichome density is strikingly variable among natural populations (e.g., [2, 4]). Despite substantial progress in the genetic dissection of trichome development , how trichome number is modulated in natural populations remains enigmatic. Here, we show that the ENHANCER OF TRY AND CPC 2 (ETC2) from the single-repeat R3 MYB family is the major locus determining trichome patterning in natural Arabidopsis populations. Our study identifies a single amino acid substitution in ETC2 (K19E) as the causal quantitative trait nucleotide (QTN). We suggest that this amino acid replacement might affect the stability of the ETC2 repressor, which results in a reduced trichome number. This is consistent with the view that morphology can evolve by coding changes that can subtly modulate protein activity as well as cis-regulatory changes that alter expression patterns.