Unlike passive humor appreciation, the neural correlates of real-time humor creation have been unexplored. As a case study for creativity, humor generation uniquely affords a reliable assessment of a creative product’s quality with a clear and relatively rapid beginning and end, rendering it amenable to neuroimaging that has the potential for reflecting individual differences in expertise. Professional and amateur “improv” comedians and controls viewed New Yorker cartoon drawings while being scanned. For each drawing, they were instructed to generate either a humorous or a mundane caption. Greater comedic experience was associated with decreased activation in the striatum and medial prefrontal cortex (mPFC), but increased activation in temporal association regions (TMP). Less experienced comedians manifested greater activation of mPFC, reflecting their deliberate search through TMP association space. Professionals, by contrast, tend to reap the fruits of their spontaneous associations with reduced reliance on top-down guided search.