Bacteriophages are the most abundant entities found within the human gastrointestinal tract, yettheir interaction with bacterial hosts remain poorly understood, particularly with respect to CRISPRCas immunity. Here, we show that the Type IC CRISPRCas system in the prevalent gut Actinobacterium Eggerthella lenta i s active both transcriptionally and catalytically, cleaving foreign and self DNA. Comparative analyses of E. lenta CRISPRCas systems across genomes and metagenomes revealed two distinct clades according to their shared cas gene sequence similarity and spacer content. To identify putative CRISPR targets, we assembled a human virome database (HuVirDB) encompassing 1,831 samples, revealing matches for the majority of the identified spacers, including “hypertargeted” phage with as many as 96 protospacers. Modeling observed spacer/protospacer pairs, we mapped positional mismatch tolerance in crRNAs. This work emphasizes the utility of merging computational and experimental approaches for determining the function and targets of human gut bacterial CRISPRCas systems.