Piezo1 is a cation selective channel in eukaryotes, and Xerocytosis is a disease of red cells that has been mapped to mutations in the gene encoding Piezo1. We introduced these mutations into a cloned human Pieoz1 and measured their effects on the channel kinetics. Substituting arginine for methionine at position 2225 (M2225R), or a hisitidine for arginine at position 2455 (R2455H) slowed inactivation. This behavior is true in whole cell recordings and cell-attached and outside-out current patches. At position 2455, introduction of lysine, a conservative amino acid change for arginine, we were unable to restore inactivation, indicating that a charge movement at that location in the membrane field is not involved in voltage-dependent inactivation. Cotransfection of cells with Piezo1 and MscL allowed us to estimate the relative stress sensitivity, equivalent to the mean area change, of both channels in a single patch. Surprisingly, the slope sensitivities of both channels were similar, indicating that the dimensional changes for opening Piezo1 is close to that of MscL at 6.5 nm2. We also demonstrate that the inhibitor of mechanical channels, GsMTx4, also blocks currents from mutant channels. The biophysics of Piezo dysfunction shows that the channel stays open longer than in the wild type and likely affects red cell volume regulation by allowing an excess influx of calcium.Supported by the National Institutes of Health and the Department of Defense