With the development of optimal surface cleaning techniques by cluster ion beam sputtering, certain applications of SIMS for analyzing cells and tissues have been actively investigated. For this report, we collaborated with bio-medical scientists to study bio-SIMS analyses of skin and cancer tissues for biomedical diagnostics. We pay close attention to the setting up of a routine procedure for preparing tissue specimens and treating the surface before obtaining the bio-SIMS data. Bio-SIMS was used to study two biosystems, skin tissues for understanding the effects of photoaging and colon cancer tissues for insight into the development of new cancer diagnostics for cancer. Time-of-fight SIMS imaging measurements were taken after surface cleaning with cluster ion bombardment by Bi-n or C-60 under varying conditions. The imaging capability of bio-SIMS with a spatial resolution of a few microns combined with principal component analysis reveal biologically meaningful information, but the lack of high molecular weight peaks even with cluster ion bombardment was a problem. This, among other problems, shows that discourse with biologists and medical doctors are critical to glean any meaningful information from SIMS mass spectrometric and imaging data. For SIMS to be accepted as a routine, daily analysis tool in biomedical laboratories, various practical sample handling methodology such as surface matrix treatment, including nano-metal particles and metal coating, in addition to cluster sputtering, should be studied. (C) 2008 Elsevier B. V. All rights reserved.