The American Cancer Society (ACS) defines cancer survivorship as beginning at diagnosis with cancer and continuing for the balance of life and views quality of life (QOL) as a key outcome. In this article, the authors describe the rationale, methodology, and sample characteristics of the 2 ACS Studies of Cancer Survivors (SCS): 1) a longitudinal study identifying and surveying survivors approximately 1 year postdiagnosis that includes plans to resurvey the panel at 2 years, 7 years, and 12 years postdiagnosis to identify predictors of QOL; and 2) a cross-sectional study of QOL among 3 separate cohorts of survivors who were approximately 3 years, 6 years, and 11 years postdiagnosis at the time of data collection. Survivors of prostate, breast, lung, colorectal, bladder, skin, kidney, ovarian, and uterine cancers and of non-Hodgkin lymphoma were sampled from 25 different central cancer registries, with African-American and Hispanic survivors over sampled. Survivors completed either mail or telephone surveys that described their physical, psychological, social, and spiritual functioning. The overall recruitment rate was 34.0%; 15411 participants completed surveys, of whom 40.1% had a high school education or less and 19.4% were racial/ethnic minorities. The SCS surveys provide a large diagnostically, geographically, and demographically diverse database on cancer survivorship that was designed to overcome some of the limitations of past research. Future reports will compare QOL of survivors at different well-defined times postdiagnosis, investigate the issues of understudied populations and diagnostic groups, and describe survivor QOL at state levels. Insights valuable to those considering registry-based studies are offered on issues of ascertainment, sampling, and recruitment. Cancer 2007. © 2006 American Cancer Society.