Botanical dietary supplements with a history of safe human use may not require the same level of toxicity testing as synthetic pharmaceutical drugs. Most of the documented examples of acute toxicity caused by botanical dietary supplements have been caused by the substitution of toxic plants for the desired species, probably through misidentification or production errors, or by contamination with pharmaceutical agents, either as a result of poor manufacturing practices or adulteration. Although more difficult to document, chronic toxicities attributed to botanical dietary supplements may be caused by contamination by heavy metals, pesticides, or microbes or by inherent properties of constituents of the botanicals themselves. Like drug-drug interactions, botanical-drug interactions can also be a source of toxicity. Most of these toxicity problems may be prevented by implementing good agricultural practices and good manufacturing practices and applying existing toxicity testing similar to those used in drug development or new toxicity assays under development based on proteomics, genomics, or metabolomics.