Diagnosing the 'primary progressive' form of multiple sclerosis (PPMS) requires assurance that other conditions that might cause a chronic inflammatory neurodegenerative central nervous system (CNS) disease have been ruled out. Both imaging and pathological studies have shown that this form of MS tends to be less inflammatory compared with either the relapsing-remitting or secondary progressive types. There are therefore many conditions that cause a slowly progressive wasting of the CNS that might be confused with MS. The new MS diagnostic scheme has made the presence of 'typical' MS abnormalities in the cerebrospinal fluid (CSF) a mandatory first criterion, but there may well be individuals that still have PPMS even in the absence of a typical MS CSF. Here we explore what the CSF can tell about an individual's disease process and outline the current state of the art in terms of CSF analysis. Used properly, the CSF can be very helpful in clarifying a diagnosis of PPMS.