Multiple sclerosis (MS) is diagnosed on the basis of clinical findings. The diagnosis requires the appearance of lesions separated in time and space and the exclusion of other symptoms that imitate MS. There are many classifications based on clinical presentation. These criteria have been replaced by criteria that include subclinical deficit seen on threedimensional analysis of the EMP (visual, brainstem auditory and somatosensory) or the MRI of CNS. As techniques for CSF analyses have improved, like the oligoclonal bands (OCBs) and the intrathecal immunoglobulin G (IgG) production, a new category has been created - MS supported by laboratory tests that are included in Poser’s diagnostic criteria for MS. In 2001 the McDonald criteria were recommended, and in 2005 and 2010 they were revised. They were created with the purpose to make the MS diagnosis more exact and well-timed. Many diseases can be similar to the multiphasic syndrome of CNS with relapse remitting course in young adults. In recent times diagnostic is eased by the use of MRI. It is considered the most sensitive imaging modality for diagnosing sensitivity of imaging. Sensitivity of imaging is 93% and it can be seen in determining the number, the size and the location of lesions. Despite high sensitivity in diagnosing MS, typical discrete multifocal lesions of white matter CNS seen on MRI are not specific only for MS. Many diseases show identical lesions on MRI imaging. Some examples of these diseases are: variants of MS (Charcot, Devic, Schilder, and Marburg), the process of physiological ageing, Alzheimer dementia, migraine, subcortical atherosclerotic encephalopathy (Binswanger disease), leukodystrophy, encephalitis, (provoked by viruses, spirochete, microbacteria of tuberculosis). Particular caution is needed in patients with clinical picture compatible with MS, and identical multiple lesions of white matter on MRI, but with normal CSL findings. In that case, it is necessary to perform further tests in order to get the final diagnosis. Difficulties in differential diagnosis are caused by neurological diseases which are similar to MS even in clinical and MRI results including CSL findings. No single test helps to establish or exclude an MS diagnosis. MS and other less frequent diseases are diagnosed only after a large number of diagnostic tests.