We discuss the potential of cluster ion beams for overcoming difficulties experienced within molecular analysis in conventional static secondary ion mass spectrometry (SIMS). Consideration of secondary ion yield, surface damage and molecular depth profiling is included. Examples of the greatly increased secondary ion yields from 'real world' samples such as bacterial membranes are illustrated, the increase in information then benefiting multivariate analysis techniques such as principal component analysis (PCA). The increased efficiency of secondary ion formation with cluster beams, in conjunction with the reduced subsurface damage associated with C-60 bombardment is exemplified using a depth profile through a phospholipid layer, where molecular information is obtained even following doses of 2 x 10(15) ions/cm(2). This is developed further to the identification of molecular ions from the interior of etched cells. Challenges that cannot be solved solely by increased secondary ion yields and low sample damage have been considered and complications due to the influence of matrix effects along with the effect of salt concentration on the fate of molecular signals in depth profiles of biomaterials have been investigated. (c) 2006 Elsevier B.V. All rights reserved.