Differentiating neuropsychiatric Lyme disease from a primary psychiatric disorder can be a daunting task. This article describes how functional brain imaging and neuropsychological testing can be particularly valuable in helping to make diagnostic distinctions. In addition to a review of the relevance of functional imaging to neuropsychiatry in general, recent findings are presented regarding the use of single photon emission computed tomographic (SPECT) imaging in Lyme disease.