An estimated 162,460 people will die of lung cancer in the United States in 2006, making it the leading cause of cancer deaths. Small cell lung cancer (SCLC) accounts for 20% of all lung cancers and exhibits aggressive behavior with early metastases. Current treatments yield five-year survival rates of 5 to 10%, indicating a need for novel therapeutic approaches. Histone deacetylase inhibitors (HDACIs) represent a new class of anticancer agents. Trichostatin A (TSA), an HDACI, has been shown to inhibit growth in several cancers. We hypothesized that TSA may inhibit proliferation of SCLC cells. Human SCLC DMS53 cells were treated with TSA (0 to 400 nM). Light microscopy was used to assess changes in cell morphology. Western analysis was performed for acetylated histone 4 to confirm HDAC inhibition. The effect of TSA treatment on cellular growth was measured by the MTT assay. Finally, levels of BCL-2, cleaved poly(ADP-ribose) polymerase, p21, and p27 proteins were measured to look for induction of cell cycle arrest and/or apoptosis. DMS53 cells treated with TSA underwent dramatic changes in cell appearance. Treated cells assumed round and spindle shapes with distinct cellular borders. Western analysis demonstrated increased levels of acetylated histone 4. TSA treatment resulted in a dose-dependent inhibition of growth. Lastly, elevated p21, p27, and cleaved poly(ADP-ribose) polymerase along with decreased BCL-2 protein levels were observed. TSA causes morphological differentiation and dose-dependent inhibition of cell growth via cell cycle arrest and subsequent apoptosis. This suggests that TSA and other HDACIs may represent a new potential therapy for patients with SCLC.