Cell culture-based techniques are employed worldwide to assess risks to optimize design and handling of materials. Nano-scale particles particularly pose a challenge to the predictability of toxicity. This is due to the interplay of several factors including size, shape, surface properties, micro-environment, charge, electronic species etc., that affect the degree of cellular stress. Numerous assays could be employed to understand the nature of toxicity. Some of these include cytotoxicity, metabolic kinetics, modulation in cellular morphology. Various models such as primary cell culture and cell lines can also be employed that best suits a study. Signaling cascades could also be monitored in better understanding cellular responses holistically. Fluorescence microscopy can further be attempted in studying spatial and temporal variations of bio-markers. Ultimately any plethora of dose-response data, need to be streamlined for developing toxicity evaluation protocols that are accurate, cost effective and time saving.