The gut microbiome and circadian rhythms (CRs) both exhibit unique influence on mammalian hosts and have been implicated in the context of many diseases, particularly metabolic disorders. It has become increasingly apparent that these systems also interact closely to alter host physiology and metabolism. However, the mechanisms that underlie these observations remain largely unknown. Recent findings have implicated microbially derived mediators as potential signals between the gut microbiome and host circadian clocks; two specific mediators are discussed in this review: short-chain fatty acids (SCFAs) and bile acids (BAs). Key gaps in knowledge and major challenges that remain in the circadian and microbiome fields are also discussed, including animal versus human models and the need for precise timed sample collection.