The herquline alkaloids are characterized by their modest size, yet incredible molecular strain. Comprised of a macrocyclic core, a bridging 1,4-dicarbonyl substructure, and an unsymmetrical, highly Lewis basic piperazine at the base, these alkaloids have sparked the creativity of many synthetic chemists since their isolation nearly 40 years ago. This chapter is a memorable narrative that recounts our synthetic journey in successfully assembling herqulines B and C, which closely mirrors their biosynthetic origins. Fraught with unanticipated challenges that ultimately fueled reaction design and ingenuity, our synthetic campaign of the herqulines afforded countless lessons gained, which we expect to be instructive to the synthetic community. © 2022 Elsevier Inc.