Three-dimensional (3D) tissue-engineered models are under investigation to recapitulate tissue architecture and functionality, thereby overcoming limitations of traditional two-dimensional cultures and preclinical animal models. This review highlights recent developments in 3D platforms designed to model diseases in vitro that affect numerous tissues and organs, including cardiovascular, gastrointestinal, bone marrow, neural, reproductive, and pulmonary systems. We discuss current technologies for engineered tissue models, highlighting the advantages, limitations, and important considerations for modeling tissues and diseases. Lastly, we discuss future advancements necessary to enhance the reliability of 3D models of tissue development and disease. Impact Statement In this review, we describe recent progress in the development and application of three-dimensional (3D) tissue-engineered models of disease. We discuss common approaches to create 3D models from somatic and stem and progenitor cells using spheroids, organoids, biomaterials, and microphysiological systems. In addition, we describe the application of such systems to model various disorders, discover mechanisms of progression, and identify new therapeutics to combat disease, which will be useful for subsequent research and clinical translation.