The nature of the carbonyl and nitrogen substituents of hydroxamic acids has a major influence on the biological profile of these compounds. Hydroxamates with small groups such as methyl appended to the carbonyl and relatively large nitrogen substituents generally have longer duration in vivo, produce greater plasma concentrations, and often are more potent inhibitors of in vivo leukotriene biosynthesis than hydroxamic acids with the opposite arrangement. The structure-activity relationships that describe in vitro 5-lipoxygenase inhibitory activity and in vivo leukotriene biosynthesis inhibitory potency for a group of these hydroxamic acids were investigated. While most of the compounds examined were potent in vitro inhibitors of 5-lipoxygenase, their in vivo potencies varied widely. This discrepancy was usually attributable to differences in bioavailability. Substitution patterns are described that produce potent, orally active inhibitors of leukotriene biosynthesis.