Mechanochemistry has emerged as a transformative approach in synthetic chemistry, utilizing mechanical energy to drive chemical transformations. Its capacity to operate under solvent-free conditions reduces solvent waste, simplifies purification, and lowers the environmental footprint of chemical processes. With growing environmental awareness, mechanochemical methods are expected to become increasingly important for both synthesis and the late-stage functionalization (LSF) of active pharmaceutical ingredients (APIs). Several mechanochemical strategies for the functionalization of heterocyclic compounds, with a focus on the LSF of bioactive molecules, are presented. These include a solvent-free Tsuji– Trost allylation, an ultra-fast Wittig olefination and a direct mechanocatalytic Heck reaction. The methods are compared with established solution-based protocols, highlighting mechanochemistry’s potential for pharmaceutical synthesis. In addition, kinetic studies of solvent-free mechanochemical reactions are discussed, showing that ball-milling processes are impact-driven rather than mixing-controlled and scale linearly with single-impact energy.