Members of the transforming growth factor-β (TGF-β) family regulate cell fate decisions during early embryonic development and tissue homeostasis in the adult. Deregulation of TGF-β family signaling contributes to developmental anomalies, fibrotic disorders, tumorigenesis and immune diseases. TGF-β exerts a wide spectrum of cellular functions by activating canonical (SMAD-dependent) or non-canonical (SMAD-independent) pathways in a cell type-specific and context-dependent manner. Here, we focus on recent advances in the understanding of the mechanisms and functions of SMAD and non-SMAD pathways in physiology and pathology.