1. Large artery stiffness is a principal determinant of pulse pressure and both are related to cardiovascular mortality independently of other major risk factors. A clearer understanding of the structural and genetic processes that contribute to large artery properties may provide novel approaches to therapy. 2. Age, atherosclerosis and gender are three important factors that contribute to large artery stiffening. Each influences the artery elastic matrix and its relationship to medial smooth muscle cells. Genetic and hormonal modulation of the extracellular matrix proteins and their regulators, including matrix metalloproteinases (MMPs), may account for some interindividual differences. 3. In a study of 213 healthy individuals and 105 patients with coronary artery disease (CAD), we examined whether stromelysin-1 (MMP-3) genotype, determined by the 5A/6A promoter polymorphism, influences large artery stiffening. In healthy individuals, the 5A/5A genotype was linked with stiffer large arteries and higher systolic blood pressure compared with other genotypes. 4. Genetic variation in the extracellular matrix protein fibrillin-1, using a pentanucleotide repeat polymorphism, was assessed as a potential determinant of large artery stiffness in patients with CAD. The 2-3 genotype was associated with stiffer large arteries, higher pulse pressure and more severe CAD than other genotypes. 5. Females experience a greater increase in large artery stiffness with age than males, with a time-course suggestive of sex steroid modulation. The mechanisms mediating such gender differences have not been established, but the known regulatory role of sex steroids with respect to MMPs likely contributes. 6. The demonstration that genetic and hormonal modulation of extracellular matrix components and MMPs contributes to age, atherosclerotic and gender-related differences in large artery mechanical properties suggests these proteins may be important targets for therapy.