The sesquiterpene lactone class of natural products displays a diverse array of biological activities due to the presence of the α-methylene-γ-lactone motif. However, clinical translation of this class has been hampered by poor aqueous solubility and non-selective binding as a Michael acceptor at undesired targets. A prodrug approach has been developed to overcome these problems in which an amine is added into the α-methylene-γ-lactone to mask this group from nucleophiles and increase solubility. The medicinal chemistry of amino-derivatives of the sesquiterpene lactones is described, beginning with synthetic development, moving into pharmacological applications, and finishing with clinical translation.