Sulfur-containing natural products (S-containing NPs) exhibit diverse chemical structures and biosynthetic machineries. Unraveling the intricate chemistry of S-incorporation requires innovative and multidisciplinary approaches. In this review, we surveyed the landscape of S-containing NP biosynthetic machineries, classified the S-incorporation chemistry into four distinct classes, and highlighted each of the four classes with representative examples from recent studies. All highlighted chemistry has been correlated to the genes encoding the biosynthetic machineries of the S-containing NPs, which open new opportunities to discover S-containing NPs through genome mining. These examples should inspire the community to explore uncharted territories in NP research, promoting further advancements in both novel S-containing NP discovery and S-incorporation chemistry. Display omitted