SCCVII tumor cells that grow in vitro or in vivo as a solid tumor were used to compare and contrast geneexpression profiles with or without exposure to two doses of ionizing radiation. Exponentially growing SCCVII cell cultures and tumors (1 cm diameter) were treated with 0, 2, or 10 Gy, and RNA was collected 1, 3, 6, 12, and 24 h after treatment. Growth under in vitro conditions increased the expression of genes associated with the unfolded protein response (UPR) including ATF4, Ero-1 like, and cystathionase. Growth in vivo indicated that the HIF-1a genes were not upregulated, whereas genes such as hemoglobin alpha and crystallin alpha B were significantly upregulated. Ninety genes of 16K were found to be significantly modulated under either growth condition by radiation treatment. Gene expression was not dose dependent. Sixty percent of these genes exhibited similar modulation under both in vitro and in vivo conditions; however, 29% of the genes were modulated by radiation under in vivo conditions only. Gene-expression profiles for the same tumor cells can differ, dependent on growth conditions, underscoring the influence that the tumor microenvironment exerts on gene expression for both growth of solid tumors and their response to radiation treatment.