Abstract After introducing a typical example of the performance of C 60 clusters for the molecular depth‐profiling analysis of (bio‐)organic samples by secondary ion mass spectrometry (SIMS), this contribution reviews a few areas in which microscopic models using molecular dynamics (MD) simulations provide a better understanding and predictions in the field of organic sample sputtering. The topics considered discuss about structural effects in crystalline hydrocarbons, the sputtering of hybrid metal–organic surfaces and the influence of the cluster projectile size on molecular desorption and fragmentation. The next section of the article presents experimental studies using real‐world samples taken from technological applications in materials science to illustrate some of the strengths and weaknesses of molecular analysis and imaging of organic and biological samples by SIMS. Connections with the results of the simulations are pointed out when it is deemed appropriate. Copyright © 2010 John Wiley & Sons, Ltd.