The human sideroflexin (SFXN) gene family, also classified as solute carrier family 56 (SLC56), encodes a group of five mitochondrial transmembrane proteins (SFXN1-SFXN5) involved in key aspects of mitochondrial metabolism, cellular homeostasis, and development. SFXNs are highly conserved across eukaryotic species, with evolutionary the origin traced back to the earliest metazoans. Functionally, each of the five family members exhibits distinct functional specialization. Particularly, SFXN1 and SFXN3 facilitate mitochondrial serine transport, supporting one-carbon metabolism. SFXN2 and SFXN4 are implicated in mitochondrial iron regulation, heme biosynthesis, and iron-sulfur cluster assembly. SFXN5, predominantly expressed in the brain, is proposed to regulate citrate metabolism and immune cell functions. Mutations or dysregulation of SFXN genes have been linked to certain human diseases, including congenital sideroblastic anemia, oxidative phosphorylation disorders, neurodegenerative conditions, and cancers. Structurally, SFXNs share conserved transmembrane domains and key motifs critical for substrate transport, mitochondrial iron homeostasis, and overall mitochondrial function. The evolutionary trajectory of the SFXN family-from amino acid transport to functionally specialized roles in higher organisms-highlights their biological and clinical significance. Comparative studies across model organisms reveal both conserved and divergent functions, emphasizing their importance in health and disease. A comprehensive understanding of the SFXN family not only advances fundamental mitochondrial research but also opens avenues for novel therapeutic interventions.