With ongoing colony losses driven in part by the Varroa mite and the associated exacerbation of virus load, there is an urgent need to protect honey bees (Apis mellifera) from fatal levels of virus infection and from nontarget effects of insecticides used in agricultural settings. A continuously replicating cell line derived from the honey bee would provide a valuable tool for study of molecular mechanisms of virus – host interaction, for screening of antiviral agents for potential use within the hive, and for assessment of the risk of current and candidate insecticides to the honey bee. However, the establishment of a continuously replicating, honey bee cell line has proved challenging. Here we provide an overview of attempts to establish primary and continuously replicating hymenopteran cell lines, methods (including recent results) for establishing honey bee cell lines, challenges associated with the presence of latent viruses (especially Deformed wing virus), in established cell lines and methods to establish virus-free cell lines. We also describe the potential use of honey bee cell lines in conjunction with infectious clones of honey bee viruses for examination of fundamental virology.