The transforming growth factor beta (TGFbeta) signaling pathway regulates several biological processes including cellular proliferation, differentiation, apoptosis, migration, and extracellular matrix deposition. Ligand and receptor family members signal through two main Smad signaling branches, TGFbeta/activin to Smad2/3 (Sma and MAD-related proteins) and bone morphogenetic protein (BMP) to Smad1/5. At the molecular level, TGFbeta acts by modifying cytoskeletal organization and ultimately regulating expression of specific target genes. Germline disruption of TGFbeta signaling leads to several types of hereditary congenital malformation or dysfunction of the skeletal, muscular and/or cardiovascular systems, and to cancer predisposition syndromes. In this review, the molecular etiology of TGFbeta-associated disorders is examined, together with a discussion of clinical overlap between syndromes and possible biological explanations underlying the variable penetrance and expressivity of clinical characteristics. Increasing our understanding of the molecular etiology underlying genotype-phenotype correlations will ultimately provide a molecular-based approach that should result in better prognostic tools, smart therapeutics and individualized disease management, not only for these rare syndromes, but for more generalized disorders of the cardiovascular and musculoskeletal systems and cancer. The clinical consequence of TGFbeta signaling mutations appears to depend on environmental factors and on the basal levels of ongoing signaling transduction networks specific to each individual. In this respect, genetic background might be a central factor in determining disease outcome and treatment strategy for TGFbeta-associated diseases.