To investigate the impact of sensory-motor systems on the neural organization for language, we conducted an H2 (15)O-PET study of sign and spoken word production (picture-naming) and an fMRI study of sign and audio-visual spoken language comprehension (detection of a semantically anomalous sentence) with hearing bilinguals who are native users of American Sign Language (ASL) and English. Directly contrasting speech and sign production revealed greater activation in bilateral parietal cortex for signing, while speaking resulted in greater activation in bilateral superior temporal cortex (STC) and right frontal cortex, likely reflecting auditory feedback control. Surprisingly, the language production contrast revealed a relative increase in activation in bilateral occipital cortex for speaking. We speculate that greater activation in visual cortex for speaking may actually reflect cortical attenuation when signing, which functions to distinguish self-produced from externally generated visual input. Directly contrasting speech and sign comprehension revealed greater activation in bilateral STC for speech and greater activation in bilateral occipital-temporal cortex for sign. Sign comprehension, like sign production, engaged bilateral parietal cortex to a greater extent than spoken language. We hypothesize that posterior parietal activation in part reflects processing related to spatial classifier constructions in ASL and that anterior parietal activation may reflect covert imitation that functions as a predictive model during sign comprehension. The conjunction analysis for comprehension revealed that both speech and sign bilaterally engaged the inferior frontal gyrus (with more extensive activation on the left) and the superior temporal sulcus, suggesting an invariant bilateral perisylvian language system. We conclude that surface level differences between sign and spoken languages should not be dismissed and are critical for understanding the neurobiology of language.