The human gut microbiome represents a complex ecosystem contributing essential functions to its host. Recent large-scale metagenomic studies have provided insights into its structure and functional potential. However, the functional repertoire which is actually contributed to human physiology remains largely unexplored. Here, by leveraging recent omics datasets, we challenge current assumptions regarding key attributes of the functional gut microbiome, in particular with respect to its variability. We further argue that the closing of existing gaps in functional knowledge should be addressed by a most-wanted gene list, the development and application of molecular and cellular high-throughput measurements, the development and sensible use of experimental models, as well as the direct study of observable molecular effects in the human host.