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.