At present there is a growing interest for use of botanicals and botanical ingredients in medicines, for teas or in foods and in food supplements. In addition, a number of plant-derived food items form an integral part of regular human diets. Currently, there is an increasing awareness among safety experts and regulators of risks associated with the use of botanicals and botanical ingredients in food including food supplements. It is becoming clear that "natural" does not equal "safe" and that, in modern society, adverse health effects can occur as a result of (mis)use. With the growing awareness of these issues efforts to ensure safety of botanicals and botanical ingredients are also increasing. Several guidance documents on safety assessment of botanicals and botanical preparations to be used as ingredients in food and food supplements have been published, although, at present, relevant legislative frameworks and guidances for risk assessment are not established yet. Furthermore, when defining possible guidance documents for risk assessment of botanicals, several issues emerge that need to be developed beyond the present state-of-the-art. The present paper describes some of the issues to be considered and developed to a further extent to improve risk assessment of botanicals and botanical preparations, illustrated by examples based on some allylalkoxybenzenes. It is concluded that, for an improved and more accurate future risk assessment of botanicals, it is necessary to further develop and validate: (i) the use of the margin of exposure (MOE) concept for compounds that are both genotoxic and carcinogenic; (ii) new ways to quantify and incorporate matrix effects into risk assessment strategies; (iii) the use of analytical chemistry approaches, enabling complete chemical characterisation of complex mixtures. Defining new approaches in risk assessment would be in line with the inspiring attitude of the late Professor Robert Kroes, who, for example by supporting the threshold of toxicological concern (TTC) concept, was a pioneer for development and implementation of new paradigms in the field of risk assessment and food safety.