An internal combustion engine (ICE) is a highly nonlinear dynamic and complex engineering system whose operation is constrained by operational limits, including emissions, noise, peak in-cylinder pressure, combustion stability, and actuator constraints. To optimize today’s ICEs, seven to ten control actuators and 10−20 feedback sensors are often used, depending on the engine applications and target emission regulations. This requires extensive engine experimentation to calibrate the engine control module (ECM), which is both cumbersome and costly. Despite these efforts, optimal operation, particularly during engine transients and to meet real driving emission (RDE) targets for broad engine speed and load conditions, has still not been obtained. Methods of model predictive control (MPC) have shown promising results for real-time multi-objective optimal control of constrained multi-variable nonlinear systems, including ICEs. This paper reviews the application of MPC for ICEs and analyzes the recent developments in MPC that can be utilized in ECMs. ICE control and calibration can be enhanced by taking advantage of the recent developments in the field of Artificial Intelligence (AI) in applying Machine Learning (ML) to large-scale engine data. Recent developments in the field of ML-MPC are investigated, and promising methods for ICE control applications are identified in this paper.