The current status and challenges of small animal non-invasive imaging is briefly reviewed. The advantages of non-invasive studies on living animals versus post-mortem studies are evaluated. An argument is advanced that even in post-mortem situations, non-invasive imaging may play an important role in efficiently characterizing small animal phenotypes as well as pathology. Issues of data interpretation under anesthetized conditions in live animal studies are also reviewed. The five imaging technologies covered include CT, PET, ultrasound, MRI and optical imaging. The structural and physiological information content of these different modalities is reviewed along with the ability of these techniques to scale down for use in small mammals such as mice and rats. In general, it was found that most of these technologies scale favorably to the study of small mammals, generally providing more physiological information than when used on the larger human scale. This suggests that these types of small mammal imaging capabilities will play a very significant role in the full utilization of these important animal models in biomedical research.