Ligands of the epidermal growth factor receptor (EGF-R), known important for supporting tissue development particularly in the gut and brain, have also been implicated in regulating postnatal somatic growth. Although optimal levels of both milk-borne and endogenous EGF-R ligands are important for supporting postnatal somatic growth through regulating gastrointestinal growth and maturation, supra-physiological levels of EGF-R ligands can cause retarded and disproportionate growth and alter body composition as they can increase growth of epithelial tissues but decrease masses of muscle, fat, and bone. Apart from their indirect roles in influencing growth possibly via regulating levels of insulin-like growth factor (IGF-I) and its binding proteins (IGFBPs), EGF-R ligands can regulate bone growth and modeling directly, as they can enhance proliferation but suppress maturation of growth plate chondrocytes (for building a calcified cartilage scaffold for bone deposition), stimulate proliferation but inhibit differentiation of osteoblasts (for depositing bone matrix), and promote formation and function of osteoclasts (for resorption of calcified cartilage or bone). In addition, EGF-like ligands particularly amphiregulin can be strongly regulated by parathyroid hormone (PTH), an important regulatory factor in bone modeling and remodeling. Finally, EGF-R ligands can regulate bone homeostasis by regulating pool of progenitor cells in the bone marrow through promoting proliferation but suppressing differentiation of bone marrow mesenchymal stem cells.