Syntrophic anaerobic oxidation of methane (AOM) among spatially organized consortia of anaerobic methane-oxidizing (ANME) archaea and partner bacteria exemplifies the power of interspecies cooperative metabolic interactions that lead to novel chemical transformations in the environment. Syntrophic AOM is now recognized as a significant biological methane sink. Multiple groups of ANME, from methane-rich anoxic environments worldwide, have been described in highly ordered multi-celled consortia with one of several lineages of syntrophic bacterial partners. The pure culture isolation of these slow-growing ANME lineages has not yet been successful; however, culture-independent molecular, geochemical, and imaging approaches have elucidated aspects of their ecology and physiology, offering new insights into the potential mechanism(s) of syntrophic exchange in AOM. High-quality metagenome assembled genomes (MAGs), many curated by our team, are now available for major ANME lineages and their syntrophic bacteria, providing the essential framework for hypothesis development and refinement with in silico metabolic modeling and experimentation. In parallel, molecular, isotopic, and chemical imaging methods have also been developed or optimized by our group for tracking active environmental microorganisms and viruses, as well as assessing the specific metabolism of environmental microorganisms at the level of single cells within anoxic sediments. Additionally, archaeal genetics, including CRISPR-Cas9 gene editing, is now mature, offering an unprecedented opportunity to investigate the function of key ANME genes and their emergent phenotypes in a closely related host methanogen. With these advancements, our team of modelers and experimentalists are now uniquely positioned to advance a mechanistic and predictive framework to gain systems-level understanding of methane-based sedimentary ecosystems and syntrophic AOM partnerships. Our proposed multidisciplinary research on AOM and methane-based sediment communities encompasses three main objectives for understanding AOM syntrophy and the broader interactions with associated microorganisms and viruses, as well as their collective role as a methane sink in anoxic sediments. These objectives range in scale from intra-consortia to community-level to ecosystem: 1) to develop a molecular understanding of the mechanisms driving methane-fueled syntrophic interactions; 2) to define and characterize the microbial communities associated with methanotrophic consortia; and 3) to create integrative modeling frameworks to explore the ecophysiology of AOM consortia.