Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) of the phenylacetic acid class with anti-inflammatory, analgesic, and antipyretic properties. Contrary to the action of many traditional NSAIDs, diclofenac inhibits cyclooxygenase (COX)-2 enzyme with greater potency than it does COX-1. Similar to other NSAIDs, diclofenac is associated with serious dose-dependent gastrointestinal, cardiovascular, and renal adverse effects. Since its introduction in 1973, a number of different diclofenac-containing drug products have been developed with the goal of improving efficacy, tolerability, and patient convenience. Delayed- and extended-release forms of diclofenac sodium were initially developed with the goal of improving the safety profile of diclofenac and providing convenient, once-daily dosing for the treatment of patients with chronic pain. New drug products consisting of diclofenac potassium salt were associated with faster absorption and rapid onset of pain relief. These include diclofenac potassium immediate-release tablets, diclofenac potassium liquid-filled soft gel capsules, and diclofenac potassium powder for oral solution. The advent of topical formulations of diclofenac enabled local treatment of pain and inflammation while minimizing systemic absorption of diclofenac. SoluMatrix diclofenac, consisting of submicron particles of diclofenac free acid and a proprietary combination of excipients, was developed to provide analgesic efficacy at reduced doses associated with lower systemic absorption. This review illustrates how pharmaceutical technology has been used to modify the pharmacokinetic properties of diclofenac, leading to the creation of novel drug products with improved clinical utility.