Medical devices around the world are required to be assessed for biocompatibility to determine how the materials and manufacturing processes affect the patient based on contact type and duration. There are three basic tests in this analysis that are applicable for every medical device: cytotoxicity, sensitization, and irritation. We call these the “Big Three.” While these tests provide valuable information and protect patients, they also come at a cost in animal lives. Until recently, only cytotoxicity was performed in vitro, meaning “in glass” or not using animals; while sensitization and irritation testing still require the use of animals. Earlier in 2018 a series of articles was published in Toxicology In Vitro reporting data from an international Round Robin study to determine the reliability and predictivity of an in vitro irritation method for assessing medical devices. This data is driving change in irritation testing impacting international testing standards (ISO 10993-10) and seeking regulatory acceptance in the US. In this webinar, we will discuss the history of irritation testing, the innovations that have led to this change, the incorporation of the method into international acceptance, and where the method is in all of this process.