Abstract: The interpretation of cancer incidence trends is complicated by short-term random variation, artifactual fluctuations introduced by screening, changes in diagnosis or disease classification, completeness of reporting, and by the multiplicity of factors that may affect risk for specific cancer sites. We analyzed trends in 56 different cancer sites and subsites in the U.S. SEER registries in the period 1975–2002 using joinpoint analysis. The increase in cancer incidence for all sites combined that became evident with the inception of the SEER registries in the mid-1970s has abated since the early 1990s. Among the 15 most common cancer sites in men, sites with increasing incidence rates during the most recent time period include melanoma of the skin and cancers of the prostate, kidney and renal pelvis (kidney), and esophagus. Among women, incidence rates are increasing for leukemia, non-Hodgkin's lymphoma, melanoma, and cancers of the breast, thyroid, urinary bladder, and kidney. Incidence rates for all childhood cancers combined increased 0.6% per year from 1975 to 2002. Cancer mortality rates have decreased in the United States since 1991 in both men and in women; site-specific death rates have decreased in the most recent time period for 12 of the top 15 cancer sites in men and 9 of the top 15 cancer sites in women. Similar trends in cancer incidence and mortality have been reported in other industrialized countries. Possible reasons for these trends are discussed.