A comprehensive two-hybrid analysis has identified 28 previously unknown interactions among the proteins encoded by the vaccinia virus genome (Proc. Natl. Acad. Sci. USA, 97, 4879–4884, 2000). Vaccinia has been a useful tool in medicine and biotechnology, from its early use as the smallpox vaccine to its current uses to manufacture recombinant proteins and as a vector for recombinant vaccines against cancer and infectious disease. Using the array-based format developed by Stan Fields's laboratory at the University of Washington in Seattle (Nature, 403, 623–627, 2000), Steven McCraith and coworkers have systematically tested each of the 70,000 possible pairwise combinations of the virus's 266 putative protein-coding genes for the ability to interact in the two-hybrid assay. Although confirmation of the validity of these new interactions will be necessary, several new leads have been uncovered in the quest to gain a better understanding of vaccinia replication. For a subset of proteins, however, neither sequence homology searches nor two-hybrid analysis has revealed any information as to their function. “Developing the next generation of technologies to approach this type of problem will be one of the future challenges in the arena of genomic analysis,” states McCraith.