Environmental factors can profoundly affect the mechanical compliance and adhesion of living cells. This work explores the in vitro measurement and quantification of the mechanical compliance of individual cells interacting with: a metastable protein, zinc oxide (ZnO) and silicon dioxide (SiO2) nanoparticles (NPs), as well as the effects of in vitro focal adhesion formation on the single-cell mechanics of fibroblasts. In the first system, atomic force microscopy (AFM) based single-cell compression was found to be sufficiently sensitive to measure and quantify interactions between neuronal type cells and A[beta]42 protein, a principal component of plaque found in the brains of Alzheimer's disease patients. Cellular membrane Young's modulus, osmotic pressure change, and change in intracellular ion concentration were extracted. Of the three forms of A[beta]42 protein investigated including monomer, oligomer, and fibrillar, it was found that the oligomer had the strongest effect on cell mechanics by increasing membrane stiffness. This result is consistent with the known cytotoxicity of the oligomer. In another investigation, human aortic endothelial cells (HAECs) were exposed to ZnO and SiO2 NPs at 10 [microgram]/ml and 50 [microgram]/ml concentrations having previously been shown to induce inflammation and become cytotoxic in a dose dependent manner. By using single-cell compression, it was found that ZnO NPs induced measurable cell swelling and stiffening likely due to osmotic pressure increase and lipid peroxidation which crosslinks lipids within the membrane. At the higher concentration, a sub-population developed which showed significant morphological alteration and was mechanically softer under load, possibly due to significant lipid degradation. At low concentration, SiO2 NPs had no effect on cell mechanics. However, at higher concentration a sub-population of cells became stiffened. Three time points associated with three stages of focal adhesion formation were investigated by AFM, cell compression, and laser scanning confocal microscopy (LSCM). A new single-cell compression methodology was devised in order to measure and compare force vs. three-dimensional deformation of cells undergoing adhesion. Global cell stiffening took place correlating with increasing actin filament alignment and growth as seen with LSCM. AFM imaging revealed a transition from membrane decorated dot to rod-like structures as focal adhesion progressed.