Despite the current laboratory and instrumental approaches to the diagnosis, a patient with multiple brain lesions remains a difficult one. The reason is that these lesions can be caused by a variety of disorders, including rare ones and atypical forms. Distinguishing neoplastic lesions from non-neoplastic CNS disorders is crucial due to different treatment options. The authors report the case of a patient with multiple brain lesions, present a literature review of diseases to be differentially diagnosed with multifocal brain lesions and suggest a simple algorithm for the differential diagnosis. Timely clinical evaluation and a multidisciplinary approach are required for making a definitive diagnosis that is extremely important to start the appropriate therapy.