His research interests focus on developing new approaches for assaying small volume samples, and in applying these methods to study novel interactions between cells. Analytical approaches include capillary separations, micro and nanofluidics, miniaturized separations, NMR, and mass spectrometry. He and his group use these approaches to characterize cell-cell signaling molecules and unusual neurochemistry, including determining the presence, distribution and release of neurotransmitters, neuropeptides and a range of other molecules. Sweedler has created and validated neuropeptide characterization approaches including single-cell mass spectrometry, peptidomics protocols, and mass spectrometry imaging, and applied them to determine the peptidome of animal models ranging from mollusks, arthropods, nematodes, and a wide range of vertebrates (including rodents, primates and humans). They have reported more than 1000 novel peptides and 200 neuropeptide prohormones, the largest neuropeptide discovery effort ever reported. In terms of novel neurochemistry, they have discovered new neuromodulatory compounds such as unusual indoles and D-amino acids, and characterized their presence, actions and formation.
Sweedler has published more than 500 manuscripts and presented 500 invited lectures. He is currently the Editor-in-Chief for Analytical Chemistry.