Many electronic nicotine delivery systems (ENDS) contain multiple components which are known to contain substances which have the potential to migrate from the components and potentially be exposed to the user. Thus, the assessment of extractables and leachables (E&L) is an important part of evaluating consumer safety. Due to the nature and variety of components used in ENDS, analytical techniques need to be capable of detecting a wide range of compounds with different physiochemical properties. Some of these compounds can be highly toxic, therefore analytical methodologies need to also be capable of detecting analytes at very low parts per million levels. In addition, mass spectrometry is typically employed to support the identification of detected compounds. The purpose of this study was to determine the substances which migrate from different polymers using solvents. This data was then used to target substances in e-liquid over several timepoints. A combination of headspace gas chromatography (GC) mass spectrometry (MS), direct injection GC-MS, liquid chromatography time of flight MS and inductively coupled plasma MS, was used to screen for substances in extraction solvents and target substances in e-liquids. In addition, an untargeted screen for leachables was also performed on e-liquids. Different polymers and different grades of polymer extracted under the same conditions exhibit a widely differing extractable profile. Targeted analytes were observed at levels below toxicological concern. The untargeted leachable screen identified a number of additional compounds. Substances from polymeric materials used in ENDS can migrate into e-liquids, therefore it is important to understand the toxicity of these compounds and the potential impact on the user.