Since 1981, the Children's Cancer and Leukemia Study Group (CCLSG) has developed a series of protocols for treatment of acute lymphoblastic leukemia (ALL) in childhood. In the first randomized controlled study of the 811 protocol (1981-1983) a comparison of conventional daily 6-mercaptopurine and methotrexate with a pulsed regimen of the two drugs was performed. The superiority of the pulsed regimen was shown. In the next 841 protocol (1984-1987) a comparison of two drugs and three drugs during induction therapy was conducted. The three-drug regimen resulted in a significantly higher event-free survival (EFS) rate. In the 874 protocol (1987-1990) two regimens with or without cranial irradiation were randomly compared, and there was no significant difference between the two regimens for the standard-risk group. To further improve the EFS rate a risk group-directed protocol 911 was conducted starting in January 1991. Life-table analysis of serial CCLSG protocols revealed that the outcome of overall ALL has gradually improved with an increase of the EFS rate; 41.4% +/- 3.6% at 14 years for the 811 protocol, 51.3% +/- 3.5% at 11 years for the 841 protocol, 56.7% +/- 3.1% at 8 years for the 874 protocol, and 78.2% +/- 3.1% at 4 years for the more recent 911 protocol.