As natalizumab (Tysabri®; Elan Pharmaceuticals, Inc., Dublin, Ireland) and other disease-modifying drugs are entering the market for multiple sclerosis, the treatment repertoire is expanding beyond the established first-line treatments. This is creating new opportunities but also increasing the uncertainty in the appropriate management of this condition with its considerable societal burden. As a result, economic evaluations are increasingly influential in healthcare decision making. Seven evaluations that included natalizumab have been published to date. They largely report favorable results for this treatment compared with other drugs. However, the models used to reach these conclusions have been subjected to significant debate, owing to limited data availability as well as the methodological complexities and uncertainties in the pharmacoeconomics of multiple sclerosis. This review critically discusses the available evidence based on the cost–effectiveness of natalizumab and uses the data to explain more general issues in the evaluation of similar drugs. The review also suggests how shortcomings in current studies may potentially be addressed in the future.