<p>The emergence of new pathogenic variants and their growing resistance to existing detection and therapeutic methods have complicated the management of infectious diseases. Aptamers, with their precise molecular recognition of targets, have emerged as a promising tool to tackle this situation. Although their potential use in diagnosing and treating infectious agents have been extensively reported, yet, only few aptamers have attained optimization for clinical translation. This review outlines the key challenges hindering the aptamer optimization such as identification of suitable targets, differentiation of pathogenic strains, stability, reproducibility, and target delivery; and discusses potential strategies to overcome them. These challenges could be resolved by targeting conserved regions of pathogens and alongside using multiplex and multifunctional approaches in aptamer design. These approaches could provide more specific and reliable aptamers that act as clinically robust tool in managing infectious agents.</p>