The rising costs of drug development, reaching $4 billion per approved therapy, highlight the urgent need for more effective strategies to expand chemical diversity and target “undruggable” proteins. Inspired by Nobel laureate Sir James Black’s philosophy that “the most fruitful basis for the discovery of a new drug is to start with an old drug,” our research concentrates on skeletal editing: specifically inserting, deleting, or swapping atoms within existing frameworks to develop new therapeutic scaffolds. We have pioneered sulfur-based carbene and nitrene chemistry as a powerful platform for skeletal editing, enabling late-stage atom insertions into nitrogen-containing heterocycles, the backbone of ~85% of FDA-approved drugs. Unlike traditional carbene and nitrene methods, which require precious metals and harsh conditions, sulfenylcarbenes and sulfenylnitrenes operate under mild, metal-free conditions, tolerate sensitive functional groups, and enable the direct transformation of drug-like molecules into previously inaccessible scaffolds. These strategies streamline synthesis, broaden chemical space, and reduce environmental impact. Building on these discoveries, we are integrating our chemistry into DNA-encoded library platforms for billion-compound screening and developing novel macrocyclization methods for stapled peptides, expanding access to modalities that target protein–protein interactions. Through collaborations with academia and industry, these approaches address three converging priorities in drug discovery: reducing costs, enhancing sustainability, and promoting global health equity.