The release of sulfonamide antibiotics into the environment is alarming because the existence of these antibiotics in the environment may promote resistance in clinically relevant microorganisms, which is a potential threat to the effectiveness of antibiotic therapies. Controllable biodegradation processes are of particular significance for the inexpensive yet effective restoration of sulfonamide-contaminated environments. Cultivation-based techniques have already made great strides in successfully isolating bacteria with promising sulfonamide degradation abilities, but the implementation of these isolates in bioremediation has been limited by unknown microbial diversity, vast population responsiveness, and the impact of perturbations from open and complex environments. Advances in DNA sequencing technologies and metagenomic analyses are being used to complement the information derived from cultivation-based procedures. In this Review, we provide an overview of the growing understanding of isolated sulfonamide degraders and identify shortcomings of the prevalent literature in this field. In addition, we propose a technical paradigm that integrates experimental testing with metagenomic analysis to pave the way for improved understanding and exploitation of these ecologically important isolates. Overall, this Review aims to outline how metagenomic studies of isolated sulfonamide degraders are being applied for the advancement of bioremediation strategies for sulfonamide contamination.