Symptoms caused by bacterial, viral and malarial infections usually overlap and aetiologic diagnosis is difficult. Patient management in low-resource countries with limited laboratory services has been based predominantly on clinical evaluation and syndromic approaches. However, such clinical assessment has limited accuracy both for identifying the likely aetiological cause and for the early recognition of patients who will progress to serious or fatal disease. Plasma-detectable biomarkers that rapidly and accurately diagnose severe infectious diseases could reduce morbidity and decrease the unnecessary use of usually scarce therapeutic drugs. The discovery of microRNAs (miRNAs) has opened exciting new avenues to identify blood biomarkers of organ-specific injury. This review assesses current knowledge on the relationship between malaria disease and miRNAs, and evaluates how future research might lead to the use of these small molecules for identifying patients with severe malaria disease and facilitate treatment decisions.