We explored the application of imaging time-of-flight secondary ion mass spectrometry (TOF-SIMS) to the high-throughput analysis needed for combinatorial chemistry research. Prototypical examples include the characterization of polymer resins, which are chemically modified as part of a combinatorial library synthesis. We studied sample conditioning for various polymer matrices, linker systems, and analytes attached to the linkers and found that the hydrophilicity of the supporting substrates play a very important role in confining the signals to a localized area. We also developed protocols for the high-throughput purpose that use specially designed substrates to hold a large number of resins (as many as 10,000), which avoids cross-contamination among components. Using this approach, we are able to perform chemical assays on polymer resins at a rate of about 1-10s(-1) This analysis has equivalent chemical specificity and sensitivity to but a speed at least an order of magnitude faster than that of ESI-MS or LC-MS. (C) 2002 Elsevier Science B.V. All rights reserved.