Small-animal PET refers to imaging of animals such as rats and mice using dedicated PET scanners. Small-animal PET has been used extensively in modern biomedical research. It provides a quantitative measure of the 3-dimensional distribution of a radiopharmaceutical administered to a live subject noninvasively. In this article, we will discuss the operational and technical aspects of small-animal PET; make some comparisons between small-animal PET and human PET systems; identify the challenges of, opportunities for, and ultimate limitations in applying small-animal PET; and discuss some representative small-animal PET applications. Education objectives: After reading this article, the technologist will be able to explain the requirements and benefits of small-animal PET in biomedical research, describe the design and general characteristics of a small-animal PET system, list and describe some of the challenges of imaging small animals, and discuss several small-animal PET applications.