The extent to which data from immunohistochemical (IHC) staining are useful is critically dependent not only upon the proper performance and control of the method but also upon appropriate interpretation. A decade ago an individual pathologist may have nurtured a reasonable expectation of achieving a comprehensive understanding of the IHC literature across the whole field of pathology. Today such an expectation is clearly unreasonable with a simple Medline search of the IHC literature postdating the general adoption of antigen retrieval (arbitrarily 1996), yielding more than 100,000 "relevant" articles. The problem is compounded by enormous variability in sample preparation, by the literally thousands of antibodies that are available in catalogs, by the complexity of the tissue section environment, exactly which cells stain, or which do not, and by the subjective assessment of the presence and intensity of specific staining.This chapter describes attempts being made to address these issues. It also outlines the practical steps that may be taken to maximize effectiveness and reproducibility of IHC results within a lab. Adopting a "total test" mindset with attention to every phase of the process is the key initial step.The rapid growth of predictive markers, companion diagnostics, or advanced personalized diagnostics merely serves to underline the inadequacies of IHC and to reinforce the necessity for improved standardization, consistent interpretation, and precise quantification that almost certainly will involve the introduction of new internal and external reference standards, plus digital assistance in interpretation and quantification.