In the past few years, PET and PET/CT imaging have increasingly been used as the modalities of choice for the diagnosis, staging and restaging of malignant disease. The main reason for the wide spread use of this modality primarily lies in its ability to accurately quantify the amount of activity concentration in tissues. However there are many factors that affect the accuracy of PET quantification. These factors can be grouped into three main categories. 1) Effects that are scanner dependent, 2) effects that are dependent on patient compliance with the study protocol, and 3) effects that are dependent on the PET study conditions. In addition, the growing use of PET/CT in the past few years as the improved mode of PET imaging due to its ability to combine functional information with anatomical localization, has also introduced a new category of factors that affect the accuracy of PET quantification. All of these factors should be accounted for whenever longitudinal or multi-center studies are performed in order to insure accuracy and reliability of PET outcome measures. The aim of this paper is to identify and describe each of the factors that impact PET quantification with special emphasis on methods that are currently used or are under development to overcome them.