A skeletal mechanism (144 species) and a corresponding reduced mechanism (62 species) were developed on the basis of the most recent detailed n-heptane mechanism by Lawrence Livermore National Laboratories (LLNL, version 3.1, 2012) (Mehl et al., 2011, “Kinetic Modeling of Gasoline Surrogate Components and Mixtures Under Engine Conditions,” Proc. Combust. Inst., 33, pp. 193–200), in order to assess the mechanism's performance under various practical combustion conditions. These simplified mechanisms were constructed and validated under shock tube conditions. Three-dimensional computational fluid dynamics (3D CFD) simulations with both simplified mechanisms were conducted for the following modeling applications: ignition quality tester (IQT), diesel engine, and homogeneous charge compression ignition (HCCI) engine. In comparison with experimental data, the simulation results were found satisfactory under the diesel condition but inaccurate for both the IQT and HCCI conditions. For HCCI, the intake temperature used in the simulation had to be increased 30 K in order to be consistent with the engine data provided by Guo et al. (2010, “An Experimental and Modeling Study of HCCI Combustion Using n-Heptane,” ASME J. Eng. Gas Turbines Power, 132(2), 022801). Exploration of possible causes is conducted leading to the conclusion that refinement in the mechanism is needed for accurate prediction of combustion under IQT and HCCI conditions.