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Devised in 1999 by three Irish-American reinsurance executives from New York City, it grew from a single event to a nationwide effort in a relatively short period of time. The founders decided to turn their St. Patrick's Day party into a benefit for pediatric oncology research by shaving their heads, thereby showing solidarity with children undergoing chemotherapy treatment. Therefore, the name of the Foundation is a play on the words Bald and Patrick - going bald on St. Patrick’s Day, led to St. Baldrick’s.

Since 2000, the Foundation has raised over $20 million, with the primary grant recipient being the Children's Oncology Group (COG). This network of over 200 hospitals performs cutting-edge childhood cancer research and treats over 90% of all children with cancer in North America. In 2005, the St. Baldrick’s Foundation established the first St. Baldrick’s Fellowship to encourage promising new medical professionals to pursue pediatric cancer research as a specialty. This Fellow is now in place at Schneider Children’s Hospital in New Hyde Park, NY.