Recent research has highlighted the growing public health concern arising from
mismanagement of malarial and non-malarial febrile illnesses that present with similar clinical
symptoms. A retrospective examination of patient records suggests that a syndrome-based diagnosis
results in over-diagnosis of malaria. Consequently, interventions to mitigate the frequency of
presumptive treatment of fever in malaria-endemic settings have been sought, especially for resourcelimited
areas. Guidelines that promote the use of microbiological tests and modern diagnostic kits have
demonstrated laudable progress in the ongoing challenge of febrile illness management. However, this
has brought attention to other factors like the complication of mixed infections. These issues, which
remain significant limitations to current tools and methods in the accurate diagnosis and subsequent
therapy of febrile illnesses, call for innovative diagnostic interventions. Advancements in biomedical
research over the last decade have led to the introduction of state-of-the-art molecular techniques of
omics origin that provide the possibility of diverse applications in disease diagnostics. Here, we
present notable challenges in febrile illness management, describe currently available tools and
methods for diagnosis, and discuss the opportunities for future progress, including harnessing cuttingedge
transcriptional profiling and proteomics technology to detect host immunological signatures
during infection.