The last decade witnessed intensive efforts in drug discovery and the emergence of thousands of molecules with potential for use as therapeutic targets. However, only a few hundred of these molecules reached the stage of clinical trials, with only a handful being translated from the bench to bedside. One such example is imiquimod, an immune response modifier belonging to the imidazoquinoline family. Imiquimod was first approved by the US Food and Drug Administration for the topical treatment of anal and genital warts and actinic keratosis, and later exhibited a potent antitumor activity. This promising activity inspired the development of several imidazoquinoxaline analogues and derivatives. The present review provides a comprehensive overview of the scientific literature on the chemical synthesis of imiquimod and several of its analogues, namely EAPB0203, EAPB0503 and EABP02303. The present review also discusses their preclinical properties and mechanisms of action in the context of cancer and parasitic infections, highlighting the worthiness of translating these activities into therapeutic drugs.