Sesquiterpenes are terpene compounds, containing three isoprene units rearranged in a wide variety of structures. They occur widely in nature, not only in plants but also in fungi and marine environments. Owing to peculiar structures and diverse biological activities, they attracted great attention in pharmaceutical, medicinal chemistry and nutraceutical fields. The present chapter collects novel insights into chemistry, distribution in nature and pharmacological properties of sesquiterpenes, focusing especially on caryophyllane, lactone-type, and eremophilane subgroups, due to the growing pharmacological interest. Novel structures and alternative natural sources to be further investigated and exploited have been highlighted too. Moreover, some issues regarding toxicity risk and bioavailability of sesquiterpenes, which can limit their application in practice, have been discussed.