The discovery and study of disinfection by-products (DBPs) of health and regulatory concern in drinking water have often been hampered by the lack of appropriate analytical methods, but, with the new tools and expertise now available to the drinking water industry, there is an opportunity to plug a major gap in our knowledge of the nature and identity of these chemicals. The challenge is that less than half of the halogenated by-products resulting from the chlorination of drinking water have been identified, and even less is known about those produced in waters treated with ozone, chloramines or chlorine dioxide. For the DBPs that have been identified, very little or no occurrence data exist for the unregulated chemicals to document how often a particular DBP is formed and in what quantity. The elucidation of the nature and identity of these by-products is hindered by two complicating factors. The first is the inherent aqueous solubility of many of these compounds, which renders their efficient extraction from water difficult to achieve. The second is the lack of established identity of specific potential by-products, which complicates targeted analytical approaches. This paper reviews existing and new methodologies that attempt to overcome some of these challenges.