The present work includes findings from proof-of-principle feasibility studies on iron nanopowder combustion under idealized, enginelike, and real engine conditions. The study was conducted under the scope of recent interest in metallic nanoparticles as alternative fuels for internal combustion engines. More specifically, Fe nanoparticles with different morphologies and average primary particle sizes ranging from 25 to 85 nm were studied with respect to their oxidation characteristics via thermogravimetric analysis as well as in customized shock tube, constant-volume vessel, and compression-ignition (CI) engine configurations. Combusted powder samples were in all cases examined via in situ and ex situ techniques for the identification of combustion products and their morphologies. The findings facilitated the determination of the main phenomena involved during oxidation. The results verified that combustion of Fe nanoparticles in a slightly modified CI engine is feasible, albeit with various technological challenges related to ignition and scavenging that inhibit combustion quality.