To estimate the health risk of a specific part of the population due to an environmental factor, the exposure can be measured and consecutively evaluated by means of toxicity data from the literature. To facilitate the choice between parameters of external exposure (ExEx) versus biomarkers of exposure (BmEx), a guideline is proposed, which consists of eleven considerations. (1) Local effects (directly on airways, eyes or skin) usually require ExEx, whereas systemic effects call for BmEx. (2) Determination of the contribution of a specific, environmental source among multiple, e.g., non-environmental sources of a substance calls for ExEx. (3) The availability of a reliable exposure-response relationship for the effect considered and of a health-based limit value; theoretically a relationship based on BmEx can be more reliable. (4) The possibility to determine reliably the exposure data that are needed, depending on the time and duration of the sampling with respect to the pattern of the external exposure, on the number of samples, and the toxicokinetic properties. (5) Inconvenient route of entry points to BmEx. (6) The presence of a group at risk due to intake-related behaviour or toxicokinetics calls for BmEx. (7) In the case of non-specificity of BmEx due to other substances the increase or decrease of the effect predicting value should be evaluated. (8) Substantial probability of effects calls for BmEx. (9) Feasibility of sampling technique and reliability of the analysis. (10) Acceptance by the public points to BmEx. (11) Cost-effectiveness. Several examples illustrate this guideline.