As the global population expands and its waste increases, resource-efficient, sustainable waste-to-energy technologies are becoming critical. Multi-omic technologies—genomics, transcriptomics, proteomics, and metabolomics—give a level of understanding into the complex biological processes involved in waste degradation and bioenergy generation that had not been possible using traditional methods alone. This chapter provides a summary of recent studies that have leveraged multi-omic technologies to enhance bioenergy generation from waste resources, including agri-food waste, food waste, and industrial waste. Multi-omic approaches can improve conversion efficiencies in biorefineries and wastewater treatment processes, and develop new bioenergy approaches, by understanding factors such as microbial community interactions, nutrient availability, metabolic pathways, and regulatory pathways. In addition, predictive modeling now can be done through bioinformatic tools and machine learning to identify microbial taxa and metabolic pathways that may increase energy yield. A multi-omic approach has the potential to facilitate the waste-to-energy process, converting waste into valuable energy resources and enhancing sustainability and a circular bioeconomy in the future.