HBO treatment affects many of the components involved in I/R injury, including PMNL function, endothelial CAM expression, NO production, NOS expression, cellular energetics, lipid peroxidation, and microvascular blood flow. Given the variety of models used to study the individual components involved in I/R injury, it is difficult to determine which is the predominant factor affected by HBO and which generates the observed beneficial outcomes in most systems. Experimental differences in the types of I/R injury, the timing of HBO treatment relative to the I/R injury (before, during, after, or delayed), the duration of HBO treatment pressure and duration, and the time of outcome measurements confound our ability to compare studies and determine the key beneficial factor. Upon review, it is likely that the sum of many of these effects is responsible for the final outcome. We have been presented with many of the pieces of the puzzle with respect to the beneficial effect of HBO in ischemia-reperfusion injury states. Hopefully, future studies will unite them into a clear picture of the basic mechanism(s) responsible for the benefits of hyperbaric oxygen therapy.