How are signed languages processed by the brain? This review briefly outlines some basic principles of brain structure and function and the methodological principles and techniques that have been used to investigate this question. We then summarize a number of different studies exploring brain activity associated with sign language processing especially as compared to speech processing. We focus on lateralization: is signed language lateralized to the left hemisphere (LH) of native signers, just as spoken language is lateralized to the LH of native speakers, or could sign processing involve the right hemisphere to a greater extent than speech processing? Experiments that have addressed this question are described, and some problems in obtaining a clear answer are outlined.