In order to meet the continuously stringent standards in terms of pollutant emissions and fuel consumption from combustion engines of road vehicles, several investigations have been recently conducted about in-cylinder techniques and aftertreatment systems. In particular, the control of the fuel injected quantity and of the center of combustion (MFB50) performed cylinder-by-cylinder can effectively provide advantages in terms of pollutant formation and fuel consumption. In the present investigation, an experimental comparison among different control strategies is performed in a heavy-duty 3.0 L Euro VI diesel engine. The first control strategy is the standard one originally implemented in the ECU, whereas the other two are referred to as model-based and pressure-based combustion controls and have been implemented by means of rapid prototyping and proper hardware device connected to the ECU. The former applies a low-throughput physical model to estimate the heat release rate and MFB50. The heat-release rate model is based on an improved version of the accumulated fuel mass approach, which requires as inputs a set of engine quantities already measured or estimated by the standard ECU (such as engine speed, rail pressure, air mass, pressure and temperature in the intake manifold, fuel injected quantities and related injection timings). The latter considers the utilization of a pressure transducer for each cylinder capable of performing the instantaneous measurement of in-cylinder pressure, from which the corresponding mass fraction burned and the actual value of MFB50 are derived. The comparison among the three control strategies in terms of fuel consumption and pollutant emissions, namely NOx, CO, HC and smoke, has been initially performed under steady-state conditions at different key-points. The investigation has then been carried out under transient conditions, in a WHTC cycle. Both model- and pressure-based methods for combustion control have shown very good performance with respect to the standard one implemented in the ECU. Pressure-based method has demonstrated to be intrinsically capable of accounting for cylinder-to-cylinder dispersion, due for instance to uneven EGR distribution in the different cylinders or uneven performance of the injectors. With reference to the pressure-based control, the robustness of the methodology has been assessed by disturbing the in-cylinder pressure signal acquired by the transducer in order to estimate the performance of the control with low-cost or aged transducers. Finally, the potential of the pressure-based method control to detect a failure or the aging of an injector has been tested by replacing one of the standard injectors with one featuring a lower injection rate for one of the injectors.