Many newly identified gene products from completely sequenced genomes are difficult to characterize in the absence of sequence homology to known proteins. In such a scenario, the context of the proteins’ functional associations can be used for annotation; overrepresented functional linkages with a certain class of proteins or members of a pathway allow putative function assignments based on the “guilt-by-association” principle. Two computational functional genomics methods, phylogenetic profiling and identification of Rosetta stone linkages, are described in this chapter, which allow assessment of functional linkages between proteins, consequently facilitating annotation. Phylogenetic profiling involves measuring similarity between profiles that describe the presence or absence of a protein in a set of reference genomes, whereas Rosetta stone fusion sequences help link two or more independently transcribed and translated proteins. Both methods can be applied to investigate functional associations between individual proteins, and can also be extended to reconstruct the genomewide network of functional linkages by querying the entire protein complement of an organism.