Microbes mediate global biogeochemical cycles through their metabolism, and all metabolic processes begin with the interaction between the microbial cell wall or membrane and the external environment. For all heterotrophs and many autotrophs, critical growth substrates and factors are present within the dilute and heterogeneous mixture of compounds that constitutes dissolved organic matter (DOM). In short, the microbe-molecule interaction is one of the fundamental reactions within the global carbon cycle. Here, I summarize recent findings from studies that examine DOM-microbe interactions from either the DOM perspective (organic geochemistry) or the microbe perspective (microbial ecology). Gaps in our knowledge are highlighted and future integrative research directions are proposed.