Bombardment of molecular solids with polyatomic projectiles allows interrogation of the sample with reduced chemical damage accumulation. Hence, it is now common to perform depth profiling experiments using a variety of substrates in a fashion similar to that reported for inorganic materials - in use for many decades. The possibility for chemical processes, however, creates a number of fundamental differences between organic and inorganic materials. To retain molecular information during beam-induced erosion, any damage accumulation must be removed at least as rapidly as it is formed. Here we discuss a number of fundamental descriptions associated with molecular depth profiling. These descriptions, which include both analytical models valuable in parameterizing the acquired signals and a molecular dynamics approach important for visualizing the action on a molecular level, point towards experimental conditions that optimize the quality of a depth profile. For example, the size and kinetic energy of the polyatomic projectile, the angle of incidence and the temperature all have significant influence on whether the important molecular ion signals are retained. Atomic force microscopy (AFM) is shown to be an essential technique for quantitative characterization of any molecular profile. Copyright © 2012 John Wiley & Sons, Ltd.