Heart and neural crest derivatives-expressed protein 1 (HAND1) and Heart and neural crest derivatives-expressed protein 2 (HAND2), members of the Twist-family of basic Helix-Loop-Helix (bHLH) proteins, act as critical transcription factors that play a key role in various developmental processes, including placental development and fetal growth during pregnancy. This review aims to explore the current understanding of HAND1 and HAND2 in pregnant maintenance and their potential implications for maternal and fetal health. We will summarize the mechanisms of action of HAND1 and HAND2 in pregnancy, their expression regulation and association with pregnancy complications such as preterm birth and preeclampsia. Furthermore, we will discuss the potential therapeutic implications of targeting HAND1 and HAND2 in pregnancy-related disorders. This review highlights the importance of HAND1 and HAND2 in pregnancy and their potential as targets for future research and therapeutic interventions of gestational disorders.