The molecular circadian clock and symbiotic host-microbe relationships both evolved as mechanisms that enhance metabolic responses to environmental challenges. The gut microbiome benefits the host by breaking down diet-derived nutrients indigestible by the host and generating microbiota-derived metabolites that support host metabolism. Similarly, cellular circadian clocks optimize organismal physiology to the environment by influencing the timing and coordination of metabolic processes. Host-microbe interactions are influenced by dietary quality and timing, as well as daily light/dark cycles that entrain circadian rhythms in the host. Together, the gut microbiome and the molecular circadian clock play a coordinated role in neural processing, metabolism, adipogenesis, inflammation, and disease initiation and progression. This review examines the bidirectional interactions between the circadian clock, gut microbiota, and host metabolic systems and their effects on obesity and energy homeostasis. Directions for future research and the development of therapies that leverage these systems to address metabolic disease are highlighted.