Interactions between chemodiverse dissolved organic matter (DOM) and biodiverse microbes are governed by a myriad of intrinsic and extrinsic factors which are not well understood. Here, we update and bridge the gap of this interdisciplinary theme comprehensively. At an ecosystem level, aquatic ecosystems dominated by algae-sourced DOM (e.g., eutrophic lake or coastal upwelling areas) harbor more biolabile DOM, such as directly assimilable monomers and readily hydrolysable biopolymers. However, other ecosystems prevailed by DOM supply from soil and vascular plants (e.g., river or wetland) have more biorefractory DOM, such as low molecular weight (LMW) residue of aliphatic C skeletons and geopolymers. A variety of heterotrophic bacteria, archaea, fungi, phagotrophic protists, and even photoautotrophic phytoplankton shows genomic and/or culturing experimental evidence of being able to process a diverse type of organics. The various biodegradable organics have different chemical structures and chemical bonds such as carbohydrates, amino acids, proteins, lignins, lipids, carboxylic acids, humic acids, hydrocarbons, and nanoplastics. Meanwhile, bio-production of metabolism intermediates and/or biorefractory organics (e.g., carboxyl-rich alicyclic molecules, CRAM) is observed despite general decay of bulk dissolved organic carbon (DOC) during bioassay experiments. In particular, emerging evidence shows that archaea contribute significantly to biomass in the marine mesopelagic zone and subsurface environments and their abundance often increases with depth in sediments. Furthermore, not only intrinsic factors (e.g., DOM composition and structure), but also extrinsic ones (e.g., sunlight and dissolved oxygen) play important roles in interplays between DOM and microbes.