In 1946, Fr. Louis Reile, S.M. founded Rho Beta Gamma (traditionally standing for Rattler Blue and Gold.) However, St. Mary's oldest organization, the Rattler Club, was organized in 1926 and recognized by the University one year later. It was originally an honor society, but, in 1947 it became a social group and eventually evolved into the Rho Chi Fraternity. The late forties and fifties saw other local fraternities/social clubs founded such as the Order of the Barons (1948), the University Club (1951), and Sigma Beta Chi (1951), currently the oldest fraternity on campus.

The 1960's saw the admittance of women to the University and a subsequent explosion of Greek activity. Local groups joined national organizations and among these were Sigma Phi Epsilon originally the Order of the Barons (1965), and Lambda Chi Alpha (1973), originally Kappa Sigma Nu (1968.) Alpha Sigma Tau (1976), originally Sigma Tau (1966) became the first National Sorority in San Antonio and on campus. Kappa Sigma was welcomed to campus in 1980, and Phi Tau Omega (1985) became Sigma Sigma Sigma (1987.) The Chi Phi Fraternity was chartered in 1988. The New United Vital organization (1987) became Delta Zeta Sorority in 1989, and most recently the women of In Pursuit of Something Challenging became the Alpha Phi International Fraternity in 1997.