One of the principal applications of toxicology data is to inform risk assessments and support risk management decisions that are protective of human health. Ideally, a risk assessor would have available all of the relevant information on (a) the toxicity profile of the agent of interest; (b) its interactions with living systems; and (c) the known or projected exposure scenarios: to whom, how much, by which route(s), and how often. In practice, however, complete information is seldom available. Nonetheless, decisions still must be made. Screening-level assays and tools can provide support for many aspects of the risk assessment process, as long as the limitations of the tools are understood and to the extent that the added uncertainty the tools introduce into the process can be characterized and managed. Use of these tools for decision-making may be an end in itself for risk assessment and decision-making or a preliminary step to more extensive data collection and evaluation before assessments are undertaken or completed and risk management decisions made. This paper describes a framework for the application of screening tools for human health decision-making, although with some modest modification, it could be made applicable to environmental settings as well. The framework consists of problem formulation, development of a screening strategy based on an assessment of critical data needs, and a data analysis phase that employs weight-of-evidence criteria and uncertainty analyses, and leads to context-based decisions. Criteria for determining the appropriate screening tool(s) have been identified. The choice and use of the tool(s) will depend on the question and the level of uncertainty that may be appropriate for the context in which the decision is being made. The framework is iterative, in that users may refine the question(s) as they proceed. Several case studies illustrate how the framework may be used effectively to address specific questions for any endpoint of toxicity.