Internal combustion engines (ICEs) currently account for approximately 25% of global power generation. Notably, this technology still plays a crucial role in a large segment of the transportation sector. In this editorial, a short overview of the latest developments and current research trends related to internal combustion engines is presented. Furthermore, the 11 contributions of this Special Issue are introduced. They cover three main topics: the use of new fuels for internal combustion engines for both automotive and railway applications; testing of additives for ICEs fed with conventional fuels; and CFD simulation applied to the analysis and design of ICE components.