One of the biggest challenges in drug development is interpretation of findings suggestive of immunostimulation, particularly when the findings are unexpected based on the known mechanism of action of the drug. Findings suggestive of immunostimulation do not necessarily preclude development of the drug. By understanding mechanism, the patient population, and species differences and by careful clinical monitoring, many of the drugs that produce immunostimulation can be successfully developed. This opinion piece describes various types of immunostimulation and a risk assessment strategy for management of unexpected immunostimulation in toxicity studies.