The TMEPAI family, composed of TMEPAI and C18ORF1, is known to inhibit transforming growth factor-β (TGF-β) signalling via its competition for binding of receptor-regulated Smad with Smad anchor for receptor activation. However, TMEPAI has also been reported to be involved in androgen receptor signalling, phosphatase and tensin homologue deleted on chromosome 10 signalling, and formation of autophagosomes in addition to degradation of TβRI (TGF-β type I receptor) through lysosomes. Thus, TMEPAI seems to act as a regulator of multiple signalling pathways. A great deal of attention has already been paid to the relationship between the TMEPAI family and tumourigenicity. In this paper, therefore, we describe recent progresses in the understanding of how the TMEPAI family physiologically contributes to cellular functions and diseases.