Computational fluid dynamics (CFD) can produce erroneous results if not used with adequate thought to several issues, some of which are discussed in the present article. Some of these issues are associated with modeling the physics, particularly the turbulence that occurs in the upper airways. For determining the location of deposition of inhaled aerosols, physical models of particle motion must also be specified and various issues associated with such models should be considered. Numerical modeling issues, including grid resolution and numerical boundary condition effects, can also profoundly affect a numerical simulation. The purpose of the present article is to highlight the importance of some of these issues in the context of modeling the fluid dynamics and particle motion in the human respiratory tract, especially for those researchers whose background is not in a discipline normally associated with CFD.