Natural and organic cosmetic and personal care products are becoming increasingly popular with consumers worldwide. Many of the new botanical ingredients being used in these topically applied products are novel to the industry and require evaluation for their safe use as expected by consumers and required by ethical companies as well as regulatory agencies. Some botanical ingredients are food or herbal medicines with a safe history of use. Other materials may be from sources not commonly used and require a more rigorous safety evaluation. We present a decision tree approach to guide risk assessments for various botanical ingredients. A straight forward pathway can be followed for materials commonly ingested. The focus here is to first assure there is sufficient safety data to move to a cosmetic use and to then assess local tolerance, i.e., irritation potential, photoxicity/photoallergy, and Type IV sensitization risk. For materials found to closely resemble food or known herbal medicines the pathway to topical tolerance may be based on detailed characterization and should be supported by reliable data including in vivo, in vitro, in silico, or human data. However, other botanicals must first be characterized by: taxonomy, cultivar, content of macro and micronutrients, chemical markers, known naturally occurring toxicants, etc. Since extracts of botanical materials can differ based on extraction procedures, etc. they may require chemical ‘fingerprinting’ or more detailed structural analysis to allow the use of in silico tools such as TTC, SAR, and metabolic profiling. For a chemical compound of known toxicity or for which a toxicological concern has been raised through in silico evaluation, skin penetration estimation must be done to determine the allowable topical dosage levels. Additional in vitro and/or in vivo testing may be required to complement in silico assessments and arrive at an adequate human safety assessment.