Significance The deadly malaria parasite, Plasmodium falciparum , has developed resistance to all currently available drugs, making the discovery of new drug targets a top priority. This eukaryotic pathogen has a unique organelle called the apicoplast that produces essential metabolites. Although the apicoplast carries its own genome, most of its proteins are encoded by the cell nucleus and it is unclear how the organelle regulates its own proteome. Here, we show that a protease complex functions as a master regulator of apicoplast biogenesis. We have shown that the essential function of the complex is determined by its proteolytic activity, regulation by a chaperone, and substrate selection. This study demonstrates the potential of the apicoplast caseinolytic-protease system as an excellent drug target.