Rats make abundant 50 kHz ultrasonic vocalizations (USVs) when they play and exhibit other positive social interactions. This response can be dramatically increased by tickling animals, especially when directed toward bodily areas toward which animals direct their own play solicitations (e.g., nape of the neck). The analysis of this system indicates that the response largely occurs in positive, playful social situations, and may index willingness for social engagement, similar to human infantile laughter, which may mature into productive adult socio-sexual behaviors. There are now enough formal similarities between rat 50 kHz USVs and human laughter, to realistically hypothesize that they are neurally and functionally homologous at the subcortical level of brain organization. To help contrast this behavior with human laughter, the available evidence concerning neural organization of human laughter is summarized from brain imaging and neuropsychological perspectives. Thus, a study of 50 kHz USVs in rats may offer an animal model for studying some of the fundamental properties of laughter circuitry in humans, and the brain mechanisms that facilitate positive social engagement, in the mammalian brain. It is proposed that further study of this phenomenon may provide a theoretical as well as empirical handle on the sources of social joy within the mammalian brain.