Selenium (Se)-containing compounds have emerged as potential therapeutic agents for the treatment of a range of diseases. Through tremendous effort, considerable knowledge has been acquired to understand the complex chemical properties and biological activities of selenium, especially after its incorporation into bioactive molecules. From this perspective, we compiled extensive literature evidence to summarize and critically discuss the relationship between the pharmacological activities and chemical properties of selenium compounds and the strategic incorporation of selenium into organic molecules, especially bioactive heterocycles and natural products. We also provide perspectives regarding the challenges in selenium-based medicinal chemistry and future research directions.