This contribution reviews the state-of-the-art in the domains of molecular imaging and depth profiling, the two methodological platforms required for 3D molecular imaging by secondary ion mass spectrometric (SIMS). Using molecular dynamics calculations, it also describes some of the mechanisms that make cluster projectiles such as C-60 so different for organic sample analysis. The discussion addresses issues that deserve proper attention on the way to 3D molecular imaging in SIMS, such as ultimate lateral resolution, limited molecular yields, chemical effects and damage, and highlights solutions currently in embryo in the many research teams concerned by 3D molecular imaging. (C) 2008 Elsevier B. V. All rights reserved.