The guinea pig maximization test (GPMT) of Magnusson and Kligman was published in 1969. Since then, a vast body of practical experience with the test has been accumulated. New information requires that certain aspects of the procedure be reevaluated, especially with regard to the interpretation of challenge results. In particular, awareness of the phenomenon of hyperirritable skin (the ‘angry back’ phenomenon) suggests that presently used controls are not always adequate and may overstate allergenicity owing to false-positive reactions. The control group should be exposed to a chemical insult at induction which provokes an inflammatory reaction comparable to the test substance. We present strategies to distinguish irritant from allergic responses. Allergic reactions should persist on rechallenge weeks later, while nonspecific irritant reactions generally fade and are irreproducible in particular animals. Finally, when a chemical is identified as a contact sensitizer of risk is necessary to estimate the relevance of the test result to usage in the real world.