Picking on someone smaller. Cytochromes P450 catalyze the hydroxylation of thousands of substrates, including alkanes. No naturally occurring P450, however, is known to oxidize the smallest alkanes, ethane and methane. Here we report the direct and selective oxidation of ethane to ethanol using dioxygen, catalyzed by a cytochrome P450 BM-3 variant engineered for high activity towards small alkanes (see scheme). Achieving P450-catalyzed oxidation of ethane is a key step in the pathway to P450-catalyzed methane oxidation and opens new opportunities for the bioconversion of natural gas to fuels and chemicals.