Medical imaging modalities to image either anatomical structure or functional processes have developed along somewhat independent paths. Functional images with single photon emission computed tomography (SPECT) and positron emission tomography (PET) are playing an increasingly important role in the diagnosis and staging of malignant disease, image-guided therapy planning, and treatment monitoring. SPECT and PET complement the more conventional anatomic imaging modalities of computed tomography (CT) and magnetic resonance (MR) imaging. When the functional imaging modality was combined with the anatomic imaging modality, the multimodality can help both identify and localize functional abnormalities. Combining PET with a high-resolution anatomical imaging modality such as CT can resolve the localization issue as long as the images from the two modalities are accurately coregistered. Software-based registration techniques have difficulty accounting for differences in patient positioning and involuntary movement of internal organs, often necessitating labor-intensive nonlinear mapping that may not converge to a satisfactory result. These challenges have recently been addressed by the introduction of the combined PET/CT scanner and SPECT/CT scanner, a hardware-oriented approach to image fusion. Combined PET/CT and SPECT/CT devices are playing an increasingly important role in the diagnosis and staging of human disease. The paper will review the development of multimodality instrumentations for clinical use from conception to present-day technology and the application software. (Nucl Med Mol Imaging 2008;42(2):153-163)