Single-atom catalysts not only maximize metal atom efficiency, they also display properties that are considerably different to their more conventional nanoparticle equivalents, making them a promising family of materials to investigate. Herein we developed a general host-guest strategy to fabricate various metal single-atom catalysts on nitrogen-doped carbon (M /CN, M = Pt, Ir, Pd, Ru, Mo, Ga, Cu, Ni, Mn). The iridium variant Ir /CN electrocatalyses the formic acid oxidation reaction with a mass activity of 12.9 Formula: see text whereas an Ir/C nanoparticle catalyst is almost inert (~4.8 × 10  Formula: see text). The activity of Ir /CN is also 16 and 19 times greater than those of Pd/C and Pt/C, respectively. Furthermore, Ir /CN displays high tolerance to CO poisoning. First-principle density functional theory reveals that the properties of Ir /CN stem from the spatial isolation of iridium sites and from the modified electronic structure of iridium with respect to a conventional nanoparticle catalyst.