Knock occurrence is a widely recognized phenomenon to be controlled during the development and optimization of S.I. engines, since it bounds both compression ratio and spark advance, hence reducing the potential in gaining a lower fuel consumption. As a consequence, a clear understanding of the engine parameters affecting the onset of auto-ignition is mandatory for the engine setup. In view of the complexity of the phenomena, the use of combined experimental and numerical investigations is very promising. The paper reports such a combined activity, targeted at characterizing the combustion behavior of a small unit displacement two-stroke SI engine operated with either Gasoline or Natural Gas (CNG).In the paper, detailed multi-cycle 3D-CFD analyses, starting for preliminary 1D computed boundary conditions, are performed to accurately characterize the engine behavior in terms of scavenging efficiency and combustion. In order to assess the accuracy of the adopted numerical approach, comparisons between numerical forecasts and experimental measurements of instantaneous in-cylinder pressure histories are carried out for both gasoline- and CNG-fueled engine operations. 3D analyses are also used to investigate the knock sensitivity of the engine to variations of spark timings in a limited set of operating conditions.The activity is simultaneously developed within a 1D modeling framework, where a detailed quasi-dimensional combustion and knock model is applied to perform a wider investigation of engine performance and knock occurrence for both Gasoline and Natural Gas fuelling. Results from 3D simulations are here used to improve the 1D simulations through a better description of scavenging and combustion processes.Once validated, 1D analyses are in particular finalized to find the knock-limited spark advance by changing both compression ratio and spark timing in order to reduce the fuel consumption. In this phase, a dedicated routine is also developed to have information on combustion related noise, which may limit fuel consumption improvements. Further confirmations on the validity of the 1D approach to the modeling of the knock onset are derived from full-3D knocking analyses over a limited set of engine operating conditions.Advantages and limitations of CNG operations of the engine are briefly pointed out at the end of the paper.