Drug resistance in malaria parasites severely erodes our ability to control disease. Combination therapies—where multiple compounds are combined to reduce the probability of resistance emerging to two or more compounds simultaneously—are the favoured solution to stemming antimalarial resistance. Thus, identifying suitable partner compounds for combinations is a priority. We sought potential partner compounds with inherent refractoriness to the spread of resistance that might better protect the primary antimalarial. We focused on azithromycin, a cheap, safe antibacterial that kills malaria parasites by blocking protein synthesis in the apicoplast—a relict plastid in malaria parasites. Selection for azithromycin resistance in rodent (Plasmodium berghei) and human (P. falciparum) malaria parasites yielded various mutations in the apicoplast-encoded gene for the 50S large ribosomal subunit protein L4 (Rpl4). P. berghei Rpl4 mutant parasites developed poorly in mosquitoes, producing aberrant oocysts and low numbers of sporozoites. P. falciparum Rpl4 mutants developed normally in mosquitoes. The azithromycin resistant mutants of both P. berghei and P. falciparum parasites could establish liver stage infections, but both species developed aberrantly, and P. berghei failed to progress to blood stage infections without massive mechanical intervention. The mutations in the apicoplast-encoded ribosomal protein Rpl4 apparently confer azithromycin resistance in the vertebrate blood phase, but the mutations confer a fitness deficit—likely reduced efficiency of apicoplast protein synthesis—that becomes a severe problem for the parasites in the highly-replicative mosquito stage (for P. berghei) and liver stage (for both P. berghei and P. falciparum). The apicoplast is more active metabolically in mosquito and liver stages than blood stage, and we hypothesise that the mutations in apicoplast Rpl4 render it less able to deliver on these metabolic needs, thus retarding parasite development. Azithromycin resistance will therefore be less likely to spread geographically, making it an attractive option as a perennial partner compound to protect appropriate frontline antimalarials from resistance spread.