A new middle Pleistocene record of Mustela nigripes is reported from Cathedral Cave, White Pine County, Nevada. The specimen dates to 750,000–850,000 years ago and represents one of the oldest remains recovered of the black-footed ferret. Forty-two percent of fossil faunas known to contain M. nigripes do not contain Cynomys, the common prey of black-footed ferrets in historic times. Consideration of dietary information and habitat requirements of M. nigripes and its sister taxon, M. eversmanni (steppe ferret), reveals ancestral behavioral repertoires for ferrets. We suggest that the historically documented “obligate” predator–prey relationship between M. nigripes and Cynomys was a secondary effect of colonization by black-footed ferrets of Cynomys-dominated habitats sometime in the past 800,000 years. A phylogenetic perspective on the behavior of ferrets combined with paleontological data indicates a broader range of possibilities for conservation of the black-footed ferret.