Giant molecular clouds (GMCs) are the home of the most extreme conditions and the most dramatic events found in the interstellar medium (ISM). As hosts of the densest, coldest portion of the ISM’s gas, gravitational collapse is inevitable, and leads to the formation of star clusters. These young star clusters, in turn, host massive and luminous stars that profoundly alter — and ultimately destroy — their birth clouds, by a combination of photoevaporation, radiation forces on dust, and strong shocks from winds and supernovae. Because GMCs are porous, the energy injected by massive stars also escapes to power the surrounding ISM. Given the complex array of processes involved, numerical simulations are essential to developing quantitative models of the lives and deaths of star-forming GMCs. In this talk, I will describe results from recent radiation (magneto-) hydrodynamic simulations that have helped us to understand how star-forming GMCs self-regulate, while simultaneously regulating the thermal, ionization, and turbulent states of the distant diffuse ISM.