Cancer therapies have improved significantly over the last few decades. However, most anticancer agents, while effective, often cause severe side effects to healthy tissues. To address these challenges, prodrug strategies have gained considerable attention. Prodrugs with enhanced physicochemical and pharmacological properties have facilitated the FDA approval for many drug candidates. In the context of cancer therapy, prodrugs are typically designed to be stable and inert in systemic circulation, becoming activated following distribution to cancer cells. These strategies improve the targeted delivery of cancer therapies, enhance effectiveness, reduce off-target effects, thereby offering improved tolerability and safety. This review provides an update on the recent advances in prodrug design for anticancer agents, with a focus on small molecules. It highlights prodrug approaches based on receptor-targeted, transporter-targeted, enzyme-activated, and those that take advantage of the unique properties of the tumor microenvironment.