Metronidazole constitutes a mainstay in the antimicrobial therapy of intestinal protozoa, and is also traditionally considered first-line therapy in cases where there is a requirement to treat Blastocystis, a common protist of disputable clinical significance. Many compounds have been used in attempts to eradicate the parasite, and an accumulating body of data indicates that successful antimicrobial eradication of Blastocystis is far from straightforward. This review focuses on some issues that prevent us from reaching a clear understanding of how to eradicate Blastocystis based on chemotherapeutic intervention, by focusing on conflicting reports on the efficacy of metronidazole and other compounds and study design and data limitations. The review provides a comprehensive overview of antimicrobials used to target Blastocystis, and discusses issues pertaining to drug resistance, treatment failure, and reinfection. Finally, key methodological and molecular diagnostic tools that will assist in the generation of data required to improve current knowledge are identified and discussed.