Current advancements in metagenomics and genomics have led to wide-spread discovery of new archaeal species in the last decade. Astoundingly, archaea are globally distributed and represent the predominant organisms on our planet. While we are beginning to understand the vast distribution of these organisms, we currently know very little about their biology, as ~ 30 – 80% of their genomes are unannotated. Further, many of these organisms are hard to culture. To annotate these genomes, we utilize a variety of pipelines, including sequence and structural bioinformatic predictions, and a high-throughput fosmid-based functional screen that enables discovery of enzymes based on function and not sequence or structural predictions. Importantly, the functional screen utilizes E. coli as a host to express archaeal genes, and therefore enables access to unculturable archaeal species.