Paul MacLean’s concept of epistemics—the neuroscientific study of subjective experience—requires animal brain research that can be related to predictions concerning the internal experiences of humans. Especially robust relationships come from studies of the emotional/affective processes that arise from subcortical brain systems shared by all mammals. Recent affective neuroscience research has yielded the discovery of play- and tickle-induced ultrasonic vocalization patterns (∼50-kHz chirps) in rats may have more than a passing resemblance to primitive human laughter. In this paper, we summarize a dozen reasons for the working hypothesis that such rat vocalizations reflect a type of positive affect that may have evolutionary relations to the joyfulness of human childhood laughter commonly accompanying social play. The neurobiological nature of human laughter is discussed, and the relevance of such ludic processes for understanding clinical disorders such as attention deficit hyperactivity disorders (ADHD), addictive urges and mood imbalances are discussed.