Nanotechnology exploits the fact that nanoparticles exhibit unique physicochemical properties, which are distinct from larger particles of the same composition. It follows that nanoparticles may also express distinct bioactivity and unique interactions with biological systems. Therefore, it is essential to assess the potential health risks of exposure to nanoparticles to allow development and implementation of prevention measures. One of the biggest challenges facing the field of nanotoxicology is the huge variety of different nanoparticle types possessing a variety of properties. Genetic Luciferase Reporter System or Reporter gene assay has become an invaluable tool in studies of gene expression. This is achieved by linking the firefly luciferase gene to a promoter sequence. Luciferase assays are quick, highly sensitive, have wide dynamic range, and are cheap to perform. Because of their simplicity and versatility, and because of the absence of endogenous luciferase activity in most cell types, this test can be applied for testing a large variety of nanomaterials for their pathogenic or carcinogenetic effects on a wide range of mammalian cells. This system is an ideal early-stage toxicology tool for screening nanomaterials. Here we describe the Genetic Luciferase Reporter System as the method for detecting alteration of gene expression in response to external stimuli (e.g., nanoparticles).