Proteomic and metabolomic changes associated with cellular metabolism are important metabolic indicators that can give insight into cellular function. Metabolites are small molecular weight cellular components of mass typically <1500 Da and well suited for detection using ToF‐SIMS. The advent of cluster ion beams, such as bismuth (Bi n ) and C 60 , as primary ion sources, has improved the sputtering efficiencies, with higher secondary ion yields and lower damage cross sections, enabling better detection of these components. However, the spectral information is dominated by fragment peaks, matrix interference and preferential ionizations making it challenging to apply time‐of‐flight secondary ion mass spectrometry for non‐targeted analyses. In this investigation, the challenges in detecting metabolic changes in cells and tissues are discussed, and areas that need further development are highlighted. Copyright © 2012 John Wiley & Sons, Ltd.