This paper aims at introducing an original, simulation based, methodology to optimize air charging system of a medium speed engine in order to improve fuel consumption/NO_x trade-off, over a given load profile. A preliminary study is performed on an engine originally equipped with fixed geometry turbocharger (TC) matched at full load. It shows that improving the TC efficiency has a positive impact at matching point but an adverse effect at lower loads. Therefore matching the TC at part load is more promising when the whole engine operating range is considered. However, this requires using a relief system to avoid unacceptable peak firing pressure at full load, and may alter regulated NO_x emission. A new, original methodology is then proposed. Using an advanced existing algorithm, it allows for simultaneous optimization of injection timing, main TC matching and relief system design. The objective is to minimize fuel consumption averaged over several operating points (corresponding to actual load profile). At the same time, NO_x emission, evaluated on regulatory cycle, is kept below a given limit and others reliability constrains are fulfilled. The methodology is assessed with several case studies: – First, various relief systems (blow-off valve, waste gate (WG) and parallel sequential turbocharger (PTC)) are compared on a given load profile – Then, the dimensioning of a TC+WG system is performed for two different load profiles In both cases, the proposed methodology leads to a charging system design customized for a given user profile, which enables a significant fuel consumption reduction.