The use of multivariate analysis (MVA) methods in the processing of time-of-flight secondary ion mass spectrometry (ToF-SIMS) data has become increasingly more common. MVA presents a powerful set of tools to aid the user in processing data from complex, multicomponent surfaces such as biological materials and biosensors. When properly used, MVA can help the user identify the major sources of differences within a sample or between samples, determine where certain compounds exist on a sample, or verify the presence of compounds that have been engineered into the surface. Of all the MVA methods, principal component analysis (PCA) is the most commonly used and forms an excellent starting point for the application of many of the other methods employed to process ToF-SIMS data. Herein we discuss the application of PCA and other MVA methods to multicomponent ToF-SIMS data and provide guidelines on their application and use.