Histopathologic scoring is a tool by which semiquantitative data can be obtained from tissues. Initially, a thorough understanding of the experimental design, study objectives, and methods is required for the pathologist to appropriately examine tissues and develop lesion scoring approaches. Many principles go into the development of a scoring system such as tissue examination, lesion identification, scoring definitions, and consistency in interpretation. Masking (aka “blinding”) of the pathologist to experimental groups is often necessary to constrain bias, and multiple mechanisms are available. Development of a tissue scoring system requires appreciation of the attributes and limitations of the data (eg, nominal, ordinal, interval, and ratio data) to be evaluated. Incidence, ordinal, and rank methods of tissue scoring are demonstrated along with key principles for statistical analyses and reporting. Validation of a scoring system occurs through 2 principal measures: (1) validation of repeatability and (2) validation of tissue pathobiology. Understanding key principles of tissue scoring can help in the development and/or optimization of scoring systems so as to consistently yield meaningful and valid scoring data.