The selective insertion of oxygen into non-activated organic molecules has to date been considered of utmost importance to synthesize existing and next generation industrial chemicals or pharmaceuticals. In this respect, the minimal requirements and high activity of fungal unspecific peroxygenases (UPOs) situate them as the jewel in the crown of C–H oxyfunctionalization biocatalysts. Although their limited availability and development has hindered their incorporation into industry, the conjunction of directed evolution and computational design is approaching UPOs to practical applications. In this review, we will address the most recent advances in UPO engineering, both of the long and short UPO families, while discussing the future prospects in this fast-moving field of research.