Redox enzymes have tremendous potential as catalysts for preparative organic chemistry. Their usually high selectivity, paired with their catalytic efficiency under mild reaction conditions, makes them potentially very valuable tools for synthesis. The number of interesting monooxygenases, dehydrogenases, reductases, oxidases, and peroxidases is steadily increasing and the tailoring of a given biocatalyst is more and more becoming standard technology. However, their cofactor dependency still represents a major impediment en route to true preparative applicability. Currently, three different approaches to deal with this ‘cofactor challenge’ are being pursued: using whole cells, biomimetic approaches comprising enzymatic cofactor regenerations systems, and ‘unconventional’ nonenzymatic regeneration. The latter technique offers the promise of enabling simple, easily applicable, and robust reaction schemes, for example, by circumventing the ‘cofactor challenge’ and introducing redox power directly to the enzyme’s active sites.