Aptamers, developed through SELEX (systematic evolution of ligands by exponential enrichment), are generally short oligonucleotide molecules with remarkable specificity and binding affinity to diverse biological targets. These molecules have shown promise across such fields as biosensing, molecular diagnostics, and bioimaging. However, while conventional aptamer selection strategies predominantly emphasize binding affinity, they overlook the broader spectrum of potential biological functionalities. This oversight results in aptamers that frequently exhibit limited capacity for direct biological regulation. This inherent limitation in the selection process significantly constrains both the widespread application of aptamers across diverse fields and their therapeutic potential as direct drug candidates. Functional SELEX represents an advancement by refining selection library construction and selection processes to create F-aptamers that integrate precise molecular recognition with specific biological activities. F-aptamers hold transformative potential as therapeutic agents, diagnostic tools, and molecular regulators, marking a significant step forward in biomedical applications. This minireview critically assesses recent developments in F-aptamer SELEX strategies, addressing challenges and exploring opportunities for future research in this dynamic field.