To understand human development and disease, as well as to regenerate damaged tissues, scientists are working to engineer certain cell types in vitro and to create 3D microenvironments in which cells behave physiologically. Single-cell genomics (SCG) technologies are being applied to primary human organs and to engineered cells and tissues to generate atlases of cell diversity in these systems at unparalleled resolution. Moving beyond atlases, SCG methods are powerful tools for gaining insight into the engineering and disease process. Here we discuss how scientists can use single-cell sequencing to optimize human cell and tissue engineering by measuring precision, detecting inefficiencies, and assessing accuracy. We also provide a perspective on how emerging SCG methods can be used to reverse-engineer human cells and tissues and unravel disease mechanisms.