antimicrobial peptides polymorphic toxins and selfnonself recognition systems in archaea an untapped armory for intermicrobial conflicts numerous diverse highly variable defense and offense genetic systems are encoded in most bacterial genomes and are involved in various forms of conflict among competing microbes or their eukaryotic hosts here we focus on the offense and selfversusnonself discrimination systems encoded by archaeal genomes that so far have remained largely uncharacterized and unannotated specifically we analyze archaeal genomic loci encoding polymorphic and related toxin systems and ribosomally synthesized antimicrobial peptides using sensitive methods for sequence comparison and the guilt by association approach we identified such systems in 141 archaeal genomes these toxins can be classified into four major groups based on the structure of the components involved in the toxin delivery the toxin domains are often shared between and within each system we revisit halocin families and substantially expand the halocin c8 family which was identified in diverse archaeal genomes and also certain bacteria finally we employ features of protein sequences and genomic locus organization characteristic of archaeocins and polymorphic toxins to identify candidates for analogous but not necessarily homologous systems among uncharacterized protein families this work confidently predicts that more than 1600 archaeal proteins currently annotated as hypothetical in public databases are components of conflict and selfversusnonself discrimination systemsimportance diverse and highly variable systems involved in biological conflicts and selfversusnonself discrimination are ubiquitous in bacteria but much less studied in archaea we performed comprehensive comparative genomic analyses of the archaeal systems that share components with analogous bacterial systems and propose an approach to identify new systems that could be involved in these functions we predict polymorphic toxin systems in 141 archaeal genomes and identify new archaeaspecific toxin and immunity protein families these systems are widely represented in archaea and are predicted to play major roles in interactions between species and in intermicrobial conflicts this work is expected to stimulate experimental research to advance the understanding of poorly characterized major aspects of archaeal biology