The study of regeneration in Drosophila imaginal discs provides an opportunity to use powerful genetic tools to address fundamental problems pertaining to tissue regeneration and cell plasticity. We present a historical overview of the field and describe how the application of modern methods has made the study of disc regeneration amenable to genetic analysis. Discs respond to tissue damage in several ways: (a) Removal of part of the disc elicits localized cell proliferation and regeneration of the missing tissue. (b) Damage at specific locations in the disc can cause cells to generate disc-inappropriate structures (e.g., wing instead of leg), a phenomenon known as transdetermination. (c) Diffuse damage to imaginal discs, results in compensatory proliferation of surviving cells. Candidate-gene approaches have implicated the JNK, Wingless, and Hippo pathways in regeneration. Recently developed systems will enable extensive genetic screens that could provide new insights into tissue regeneration, transdetermination and compensatory proliferation.