The association between Euprymna scolopes, the Hawaiian bobtail squid, and Vibrio fischeri, a bioluminescent bacterium, has served as a model for beneficial symbioses for over 25 years. The experimental tractability of this association has helped researchers characterize many of the colonization events necessary for symbiosis. Recent technological advances, such as the sequenced genome of V. fischeri, DNA microarrays, and high-throughput transcriptomics and proteomics, have allowed for the identification of host and symbiont factors that are important in establishing and maintaining specificity in the association. We highlight some of these findings pertaining to quorum sensing, luminescence, responses to reactive oxygen and nitrogen species, recognition of microbe-associated molecular patterns by the innate immune system of the host, and a diel rhythm that helps regulate the symbiont population. We also discuss how comparative genomics has allowed the identification of symbiont factors important for specificity and why sequencing the host's genome should be a priority for the research community.