Dual submicromolar trypanocidal-antiplasmodial compounds have been identified by screening and chemical synthesis of 4-aminoquinoline-based heterodimeric compounds of three different structural classes. Inhibition of the enzyme trypanothione reductase seems to be involved in the potent trypanocidal activity of these heterodimers but likely it is not their main biological target within Trypanosoma brucei. Regarding their antiplasmodial activity, the heterodimers seem to share the mode of action of the antimalarial drug chloroquine, which involves inhibition of the haem detoxification process. Interestingly, all of these heterodimers display good brain permeabilities, thereby being potentially useful for late stage human African trypanosomiasis and cerebral malaria. Future optimization should mainly focus on decreasing cytotoxicity and acetylcholinesterase inhibitory activity.