The number and proportion of genes with no known function are growing rapidly. To quantify this phenomenon and provide criteria for prioritizing genes for functional characterization, we developed a bioinformatics pipeline that identifies robustly defined protein families with no annotated domains, ranks these with respect to phylogenetic breadth, and identifies them in metagenomics data. We applied this approach to 271,965 protein families from the SFams database and discovered many with no functional annotation, including >118,000 families lacking any known protein domain. From these, we prioritized 6,668 conserved protein families with at least three sequences from organisms in at least two distinct classes. This project catalogs data associated with these Function Unknown Families (FUnkFams), a “most wanted” list of genes to functionally characterize.