Skin sensitisation is an important toxicological endpoint. The possibility that chemicals used in the workplace and in consumer products might cause skin sensitisation is a major concern for individuals, for employers and for marketing. In European REACH (Registration, Evaluation, and Authorisation of Chemicals) legislation, the sensitising potential should therefore be assessed for chemicals below the 10 ton threshold. Development of methods for prediction of skin sensitisation potential without animal testing has been an active research area for some time, but has received further impetus with the advent of REACH and the EU Cosmetics Directive (EU 2003). This paper addresses the issue of non-animal based prediction of sensitisation by a mechanistic approach. It is known that the sequence of molecular, biomolecular and cellular events between exposure to a skin sensitiser and development of the sensitised state involves several stages, in particular penetration through the stratum corneum, covalent binding to carrier protein, migration of Langerhans cells, presentation of the antigen to naïve T-cells. In this paper each of these stages is considered with respect to the extent to which it is dependent on the chemical properties of the sensitiser. The evidence suggests that, although penetration of the stratum corneum, stimulation of migration and maturation of Langerhans cells, and antigen recognition are important events in the induction of sensitisation, except in certain specific circumstances they can be taken for granted. They are not important factors in determining whether a compound will be a sensitiser or not, nor are they important factors in determining how potent one sensitiser will be relative to another. The ability to bind covalently to carrier protein is the major structure-dependent determinant of skin sensitisation potential. A chemistry-based prediction strategy is proposed involving reaction mechanistic domain assignment, reactivity and hydrophobicity determination, and application of quantitative mechanistic modelling (QMM) or read-across.