Coenzymes are ubiquitous in Nature, assisting in enzyme-catalysed reactions. Several coenzymes, nicotinamides and flavins, have been known for close to a century, whereas variations of those organic molecules have more recently come to light. In general, the requirement of these coenzymes imposes certain constraints for in vitro enzyme use in biocatalytic processes. Alternative coenzymes have risen to circumvent the cost factor, tune reaction rates or obtain different chemical reactivity. This review will focus on these alternatives and their role and applications in biocatalysis.