Data obtained from national probability sample surveys provide important information on the prevalence of various health conditions and distributions of physical and biochemical characteristics of the U.S. population. The sample design of a survey specifies how sampling from a designated population over a stated period is to be accomplished. A survey's analytical objectives and interests--in particular subpopulations--affect the sample design strategy. Selected subdomains of the population often must be oversampled so that estimates can be made with acceptable precision. This article addresses sample design considerations for a national probability sample for human tissue monitoring and specimen banking. Among the sampling issues addressed are the oversampling of special populations e.g., minority groups and at-risk groups such as low income or elderly persons; geographic coverage; and sample size considerations. The sample design for a major health survey, the Third National Health and Nutrition Examination Survey (NHANES III), is used to illustrate a complex, multistage probability sample design and to highlight some of the sampling issues discussed in this article.