S-21 was a security center established in late 1975. It was a place for interrogating, detaining, and killing many Khmer Rouge cadres.

The location of the S-21 Security Center had changed several times. Initially, S-21 was located in the area of Boeung Keng Kang 3 commune, while the prisoners were detained and interrogated in a block located between Street 163 and Street 360. In late November 1975, S-21 was moved to the National Police Commission on the Pasteur Street (which is now Golden Sorya Mall). However, it was moved to the old place in January 1976. In April 1976, S-21 moved to Ponhea Yat high school, which is the site of Tuol Sleng Genocide Museum nowadays. It was easier to interrogate prisoners and prevent escape there. Houses around the compound of Ponhea Yat high school were also part of S-21. Those houses were used for interrogating, as well as for staff usage, e.g., a killing site, medicine storage, houses for arrival prisoners, as well as the home and office of Duch, chief of S-21. There was special prison outside Ponnheayat high school which was for foreigners and former S-21 staff. The killing site was later moved to Choeung Ek village as the operation was getting bigger.

The last change made to that high school made it easier to operate the S-21 security center with even greater secrecy. Staff at this center were not allowed to walk freely or make contact outside the compound at all without permission.

There were five buildings in Ponhea Yat high school. According to the office of the Co-Prosecutors of the Extraordinary Chambers in the Courts of Cambodia, there were 18,063 prisoners identified. Only 14 prisoners survived after the fall of the Khmer Rouge regime on January 7th, 1979.