CNG is at present retaining a growing interest as a factual alternative to traditional fuels for SI engines, thanks to its high potentials in reducing the engine-out emissions. Increasing thrust into the exploitation of NG in the transport field is in fact produced by the even more stringent emission regulations that are being introduced into the worldwide scenario. The present paper aims at deeply investigating into the potentials of a heavy-duty engine running on CNG and equipped with two different injection systems, an advanced single point (SP) one and a prototype multi-point (MP) one. The considered 7.8-liter engine was designed and produced to implement a SP strategy and hence modified to run with a dedicated MP system. A thorough comparison of the engine equipped with the two injection systems has been carried out at steady state as well as at transient operations. Better performances in terms of cycle-to-cycle variability were proved for the MP system despite poorer mixture homogeneity. A 0D-1D model has also been built and validated on the experimental data set to be hence exploited for investigating into different strategies both for the SP and for the MP layout. An extensive simulation has been carried out on the effects of the injection phasing on the SP system performance. Finally, as far as the MP injection system is concerned, the innovative fire-skipping or cylinder deactivation has been considered, assessing for an overall decrease in the fuel consumption of 12% at part load operations.