Microarray-based gene expression profiling of large numbers of genes or even the whole genome has only recently become possible. Several studies have employed this technology in multiple sclerosis (MS) and its animal model, experimental allergic encephalomyelitis (EAE), and although results are promising, microarray-based genomics research is still viewed with skepticism. It is often negatively perceived as a fishing expedition rather than a discovery-oriented effort that takes into account the immense complexity of diseases such as MS. Besides these conceptual concerns, technical reproducibility and the strategies to analyze and interpret the massive amounts of data present problems that can cause considerable variability between studies. In this review, we summarize existing data from different gene expression profiling studies that have been conducted in MS and EAE, discuss potential problems and propose future directions for the use of microarrays in MS.