State-of-the-art patient management frequently requires the use of non-invasive imaging methods to assess the anatomy, function or molecular-biological conditions of patients or study subjects. Such imaging methods can be singular, providing either anatomical or molecular information, or they can be combined, thus, providing “anato-metabolic” information. Hybrid imaging denotes image acquisitions on systems that physically combine complementary imaging modalities for an improved diagnostic accuracy and confidence as well as for increased patient comfort. The physical combination of formerly independent imaging modalities was driven by leading innovators in the field of clinical research and benefited from technological advances that permitted the operation of PET and MR in close physical proximity, for example. This review covers milestones of the development of various hybrid imaging systems for use in clinical practice and small-animal research. Special attention is given to technological advances that helped the adoption of hybrid imaging, as well as to introducing methodological concepts that benefit from the availability of complementary anatomical and biological information, such as new types of image reconstruction and data correction schemes. The ultimate goal of hybrid imaging is to provide useful, complementary and quantitative information during patient work-up. Hybrid imaging also opens the door to multi-parametric assessment of diseases, which will help us better understand the causes of various diseases that currently contribute to a large fraction of healthcare costs.