 The equation \(E = mc^2\) is, arguably, the most famous equation in 20th century physics. To appreciate what Einstein’s famous result is about, and what it is not about, we begin in Section 1 with a description of the physics of mass-energy equivalence. In Section 2, we survey six distinct, though related, philosophical interpretations of mass-energy equivalence. We then discuss, in Section 3, the history of derivations of mass-energy equivalence and its philosophical importance. Section 4 is a brief and selective account of empirical confirmation of Einstein’s result that focuses on Cockcroft and Walton’s (1932) first confirmation of mass-energy equivalence and a more recent, and very accurate, confirmation by Rainville et al. (2005). 