Significance We present highlights of the first complete domestic cat reference genome, to our knowledge. We provide evolutionary assessments of the feline protein-coding genome, population genetic discoveries surrounding domestication, and a resource of domestic cat genetic variants. These analyses span broadly, from carnivore adaptations for hunting behavior to comparative odorant and chemical detection abilities between cats and dogs. We describe how segregating genetic variation in pigmentation phenotypes has reached fixation within a single breed, and also highlight the genomic differences between domestic cats and wildcats. Specifically, the signatures of selection in the domestic cat genome are linked to genes associated with gene knockout models affecting memory, fear-conditioning behavior, and stimulus-reward learning, and potentially point to the processes by which cats became domesticated. Little is known about the genetic changes that distinguish domestic cat populations from their wild progenitors. Here we describe a high-quality domestic cat reference genome assembly and comparative inferences made with other cat breeds, wildcats, and other mammals. Based upon these comparisons, we identified positively selected genes enriched for genes involved in lipid metabolism that underpin adaptations to a hypercarnivorous diet. We also found positive selection signals within genes underlying sensory processes, especially those affecting vision and hearing in the carnivore lineage. We observed an evolutionary tradeoff between functional olfactory and vomeronasal receptor gene repertoires in the cat and dog genomes, with an expansion of the feline chemosensory system for detecting pheromones at the expense of odorant detection. Genomic regions harboring signatures of natural selection that distinguish domestic cats from their wild congeners are enriched in neural crest-related genes associated with behavior and reward in mouse models, as predicted by the domestication syndrome hypothesis. Our description of a previously unidentified allele for the gloving pigmentation pattern found in the Birman breed supports the hypothesis that cat breeds experienced strong selection on specific mutations drawn from random bred populations. Collectively, these findings provide insight into how the process of domestication altered the ancestral wildcat genome and build a resource for future disease mapping and phylogenomic studies across all members of the Felidae.