The mammalian circadian clock regulates a wide variety of physiological and behavioral processes. In turn, its disruption is associated with sleep deficiency, metabolic syndrome, neurological and psychiatric disorders, and cancer. At the turn of the century, the circadian clock was determined to be regulated by a transcriptional negative feedback mechanism composed of a dozen core clock genes. More recently, large-scale genomic studies have expanded the clock into a complex network composed of thousands of gene outputs and inputs. A major task of circadian research is to utilize systems biological approaches to uncover the governing principles underlying cellular oscillatory behavior and advance understanding of biological functions at the genomic level with spatiotemporal resolution. This review focuses on the genes and pathways that provide inputs to the circadian clock. Several emerging examples include AMP-activated protein kinase AMPK, nutrient/energy sensor mTOR, NAD+-dependent deacetylase SIRT1, hypoxia-inducible factor HIF1α, oxidative stress-inducible factor NRF2, and the proinflammatory factor NF-κB. These input pathways, among others that continue to be revealed, reflect the extensive interplay between the clock and cell physiology through the regulation of core clock genes and proteins. While the scope of this crosstalk is well-recognized, precise molecular links are scarce and the underlying regulatory mechanisms are not well understood. Future research must leverage genetic and genomic tools and technologies, network analysis, and computational modeling to characterize additional modifiers and input pathways. This systems-based framework promises to advance understanding of the circadian timekeeping system and may enable the enhancement of circadian functions through related input pathways.