Chemical reaction networks that transform out-of-equilibrium ‘fuel’ to ‘waste’ are the engines that power the biomolecular machinery of the cell. Inspired by such systems, autonomous artificial molecular machinery is being developed that functions by catalysing the decomposition of chemical fuels, exploiting kinetic asymmetry to harness energy released from the fuel-to-waste reaction to drive non-equilibrium structures and dynamics. Different aspects of chemical fuels profoundly influence their ability to power molecular machines. Here we consider the structure and properties of the fuels that biology has evolved and compare their features with those of the rudimentary synthetic chemical fuels that have so far been used to drive autonomous non-equilibrium molecular-level dynamics. We identify desirable, but context-specific, traits for chemical fuels together with challenges and opportunities for the design and invention of new chemical fuels to power synthetic molecular machinery and other dissipative nanoscale processes.