Many drugs are administered at sites that are remote from their site of action. The most common route of drug delivery is the oral route. The optimal physicochemical properties to allow high transcellular absorption following oral administration are well established and include a limit on molecular size, hydrogen bonding potential and adequate lipophilicity. For many drug targets, synthetic strategies can be devised to balance the physicochemical properties required for high transcellular absorption and the SAR for the drug target. However, there are drug targets where the SAR requires properties at odds with good membrane permeability. These include a requirement for significant polarity and groups that exhibit high hydrogen bonding potential such as carboxylic acids and alcohols. In such cases, prodrug strategies have been employed. The rationale behind the prodrug strategy is to introduce lipophilicity and mask hydrogen bonding groups of an active compound by the addition of another moiety, most commonly an ester. An ideal ester prodrug should exhibit the following properties: 1) Weak (or no) activity against any pharmacological target, 2) Chemical stability across a pH range, 3) High aqueous solubility, 4) Good transcellular absorption, 5) Resistance to hydrolysis during the absorption phase, 6) Rapid and quantitative breakdown to yield high circulating concentrations of the active component post absorption. This paper will review the literature around marketed prodrugs and determine the most appropriate prodrug characteristics. In addition, it will examine potential Discovery approaches to optimising prodrug delivery and recommend a strategy for prosecuting an oral prodrug approach.