Contraction of muscle is due to interaction between actin and myosin. The contractile system is anchored to the cytoskeleton. Physiological function of myosin motors and cytoskeleton was examined using transgenic mice lacking the intermediate filament protein desmin (Des-/- mice) and smooth muscle myosin heavy chain (SMMHC-/- mice). Desmin is normally expressed in all muscle types, with tissue variability. Des-/- mice are viable, but have a cardiomyopathy with increased heart weight and decreased systolic function. Lack of desmin resulted in a lower active force generation and altered contractile filament lattice structure and cellular compliance. We conclude that desmin plays a role in supporting active tension possibly by affecting force transmission or sarcomere alignment. SMMHC-/- mice survive for about 3 days after birth, and their smooth muscles can contract due to non-muscle myosins. We found that non-muscle myosins can form thick filaments and support slow contractions. Non-muscle myosin is also expressed in some adult smooth muscles (e.g. aorta) and can have a physiological role in sustained contractions of vascular muscle. Due to its efficient breeding, rapid development and characterized genome the zebrafish (Danio rerio) has become an interesting vertebrate model organism in developmental and systems biology. The larvae stage (5–7 days), when the larva is about 3 mm long, is of particular interest since the gene expression can be manipulated by an antisense approach. We have recently developed a system for studies of muscle function in the larvae and report from our first physiological characterization of mechanical and structural properties of zebrafish larvae muscles.