Natural rubber (NR) has been the material-of-choice in many medical applications including medical stoppers. However, health care providers and the general population have become more aware of NR's naturally-occurring impurities and proteins, which can result in allergenic sensitivities. As a result, medical device manufacturers, which includes the medical stopper industry, seek synthetic rubber alternatives to replace NR and are also gearing up to deal with the next wave of aggressive and sensitive drugs, stricter packaging performance requirements, and rising safety standards. This paper will compare the chemistry and performance of four rubber products that are currently used in medical stoppers, which include anionic IR, polymerized with an alkyl-lithium initiator, Ziegler-Natta IR, polymerized with titanium/aluminum catalyst, chlorobutyl rubber, and bromobutyl rubber. The criterion for the study was based on common medical stopper test protocols. The results will demonstrate that anionic isoprene rubber delivers a unique combination of advantages including the absence of natural rubber proteins present in NR, an odor-free formulation with low residual metals and no residual catalysts, low needle insertion force, and minimal risk of rubber fragmentation (coring) and medication contamination due to needle insertion.