Nanoparticles, such as carbon nanotubes (CNTs), interact with cells and are easily internalized, causing various perturbations to cell functions. The mechanisms involved in such perturbations are investigated by a systematic approach that utilizes modified CNTs and various chemical-biological assays. Three modes of actions are (1) CNTs bind to different cell surface receptors and perturb different cell signaling pathways; (2) CNTs bind to a receptor with different affinity and, therefore, strengthen or weaken signals; (3) CNTs enter cells and bind to soluble signaling proteins involved in a signaling pathway. Understanding of such mechanisms not only clarifies how CNTs cause cytotoxicity but also demonstrates a useful method to modulate biological/toxicological activities of CNTs for their various industrial, biomedical, and consumer applications.