Duchenne muscular dystrophy (DMD) is characterized by severe muscle weakness, atrophy and fibrosis causing loss of mobility and respiratory failure. The disease is caused by absence of the cytoskeletal protein, dystrophin. The mdx mouse also lacks dystrophin and is a model of DMD. Early studies of the mdx mouse found that a stretch-activated channel (SAC) was activated and we showed that blocking this channel (with Gd³⁺ or streptomycin or GsMTx-4) lowered stretch-induced intracellular Ca²⁺ and reduced muscle damage (Yeung et al. 2005). Subsequently we have found that the activation of SACs and the resulting Ca²⁺ entry can be caused by reactive oxygen species (ROS) (Gervasio et al., 2008). ROS also activate src kinase and blocking src kinase with PP2 reduced ROS-induced Ca²⁺ entry in a cell line expressing TRPC1 and caveolin 3. The source of the ROS appears to be increased expression and activity of NADPH oxidase (Whitehead et al., 2010). Our current working hypothesis is that absence of dystrophin triggers changes in multiple signaling pathways centered around the caveolae. The increased activity of NADPH oxidase is an early feature of the disease and appears to have a role in triggering the Ca influx and inflammation that characterize the early disease. A clearer understanding of the damage pathways may lead to therapeutic interventions that could reduce the severity of the muscle damage in DMD. Gervasio et al. (2008) J Cell Sci 121, 2242–2255. Whitehead et al. (2010) PLOS One, 5, e15354 Yeung et al. (2005) J Physiol 562, 367–380.