This article reviews the molecular structure, expression pattern, physiological function, pathological roles and mo- lecular mechanisms of Twistl in development, genetic disease and cancer. Twistl is a basic helix-loop-helix domain- containing transcription factor. It forms homo- or hetero-dimers in order to bind the Ndel E-box element and acti- vate or repress its target genes. During development, Twistl is essential for mesoderm specification and differentia- tion. Heterozygous loss-of-function mutations of the human Twistl gene cause several diseases including the Saethre- Chotzen syndrome. The Twistl-null mouse embryos die with unclosed cranial neural tubes and defective head mesen- chyme, somites and limb buds. Twistl is expressed in breast, liver, prostate, gastric and other types of cancers, and its expression is usually associated with invasive and metastatic cancer phenotypes. In cancer cells, Twistl is upregulated by multiple factors including SRC-1, STAT3, MSX2, HIF-la, integrin-linked kinase and NF-κB. Twistl significantly enhances epithelial-mesenchymal transition （EMT） and cancer cell migration and invasion, hence promoting cancer metastasis. Twistl promotes EMT in part by directly repressing E-cadherin expression by recruiting the nucleosome remodeling and deacetylase complex for gene repression and by upregulating Bmil, AKT2, YB-1, etc. Emerging evi- dence also suggests that Twistl plays a role in expansion and chemotherapeutic resistance of cancer stem cells. Fur- ther understanding of the mechanisms by which Twistl promotes metastasis and identification of Twistl functional modulators may hold promise for developing new strategies to inhibit EMT and cancer metastasis.