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In host-associated bacteria, surface and secreted proteins mediate acquisition of nutrients, interactions with host cells, and specificity of host-range and tissue-localization. In Gram-negative bacteria, the mechanism by which many proteins cross, become embedded within, or become tethered to the outer membrane remains unclear. The d omain of u nknown function (DUF)560 occurs in outer membrane proteins found throughout and beyond the proteobacteria. Functionally characterized DUF560 representatives include NilB, a host-range specificity determinant of the nematode-mutualist Xenorhabdus nematophila and the s urface lipoprotein a ssembly m odulators (Slam), Slam1 and Slam2 which facilitate surface exposure of lipoproteins in the human pathogen Neisseria meningitidis . Through network analysis of protein sequence similarity we show that DUF560 subclusters exist and correspond with organism lifestyle rather than with taxonomy, suggesting a role for these proteins in environmental adaptation. Cluster 1 had the greatest number of representative proteins, was dominated by homologs from animal-associated symbionts, and was composed of subclusters: 1A (containing NilB, Slam1, and Slam2), 1B, and 1C. Genome neighborhood networks revealed that Cluster 1A DUF560 members are strongly associated with TonB, TonB-dependent receptors, and predicted co-receptors such as the Slam1 lipoprotein substrates transferrin binding protein and lactoferrin binding protein. The genome neighborhood network of Cluster 1B sequences are similarly dominated by TonB loci, but typically the associated co-receptors (the presumed DUF560 substrates) are predicted to be non-lipidated. We suggest that these subclusters within the DUF560 protein family indicate distinctive activities and that Slam activity may be characteristic of Cluster 1A members but not all DUF560 homologs. For Cluster 1 DUF560 homologs we propose the name SPAM ( S urface/ S ecreted P rotein A ssociated Outer M embrane Proteins) to accommodate the potential for non-lipoprotein substrates or different activities. We show that the repertoire of SPAM proteins in Xenorhabdus correlates with host phylogeny, suggesting that the host environment drives the evolution of these symbiont-encoded proteins. This pattern of selection for specific sequences based on host physiology and/or environmental factors may extend to other clusters of the DUF560 family.