The evidence that frequency modulated (FM) 50 kHz ultrasonic vocalizations (USVs) reflect a positive emotional state in rats is reviewed. Positive emotional states in humans are measured by facial/vocal displays (e.g., Duchenne smiling and laughter), approach behavior and subjective self-reporting of feeling states. In laboratory animals, only facial-vocal displays, along with approach behavior, can be measured. FM 50 kHz USVs are uniquely elevated by hedonic stimuli and suppressed by aversive stimuli. Rates of FM 50 kHz USVs are positively correlated to the rewarding value of the eliciting stimulus. Playbacks of these vocalizations are also rewarding. The neural and pharmacological substrates of 50 kHz USVs are consistent with those of human positive affective states. By experimentally eliciting FM 50 kHz USVs, the novel molecular underpinning of positive affect can be elucidated and may be similar to those in humans. In humans, positive emotional states confer resilience to depression and anxiety, as well as promote overall health. Therefore, novel antidepressants that promote positive affect-induced resilience to depression may emerge from this research.