H1 antihistamines are widely used in the treatment of conditions such as seasonal and perennial allergic rhinitis, urticaria and angioedema, as well as being an adjunct therapy for anaphylaxis. The development of new compounds within this class of pharmacological agents is based on preclinical and clinical assessments prior to registration. Preclinical assessment of novel compounds has been advanced both by the definition of the molecular structure of the H1 receptor and by high throughput screening, which allows the definition of potent and selective candidate compounds. The elimination, in subsequent evaluations, of those compounds with potential for central nervous system and cardiotoxic effects and those with inappropriate pharmacokinetics restricts the subsequent toxicological and clinical evaluation of novel H1 antihistamines. Clinical evaluation is based initially on human volunteer studies to define pharmacodynamic, pharmacokinetic and safety parameters. Local challenge models such as in the skin or nose for oral therapy or nose and conjunctiva for topical drug development allow definition of potential dose for administration, speed of onset of activity and duration of effect, both in comparison to placebo and to reference compounds. While a range of laboratory allergen challenge models, pollen chamber challenge studies and acute ‘day in the park’ study designs have been used in the early clinical evaluation of H1 antihistaminic activity, ultimately it is the efficacy of novel compounds in naturally occurring disease that is of importance. The assessment of the magnitude and profile of clinical disease improvement in specific disease areas is thus the crucial evaluation. The appropriate selection and characterization of patients, the optimization of the trial design, dependent upon the nature of the disease, and the appropriate selection of endpoints for analysis are thus critical considerations, as well as evaluation of appropriate safety criteria.