Naivety about promiscuous, assay-duping molecules (PAINS) is polluting the literature and wasting resources in drug discovery, warn Jonathan Baell and Michael A. Walters. PAINS are compounds that interfere with assays, masquerading as drug-like binding and yielding false signals. These molecules are often overlooked by biologists and inexperienced chemists, leading to wasted time and research money. The authors highlight that PAINS can be identified through specific structures and mechanisms, such as fluorescence, aggregation, and non-specific chemical reactions. They recommend familiarizing researchers with common PAINS structures, checking the literature for known PAINS, and assessing assays to detect non-drug-like mechanisms. Despite occasional successful interactions, the authors emphasize that PAINS should be ignored, and academic drug discoverers must be more vigilant to avoid futile attempts.Naivety about promiscuous, assay-duping molecules (PAINS) is polluting the literature and wasting resources in drug discovery, warn Jonathan Baell and Michael A. Walters. PAINS are compounds that interfere with assays, masquerading as drug-like binding and yielding false signals. These molecules are often overlooked by biologists and inexperienced chemists, leading to wasted time and research money. The authors highlight that PAINS can be identified through specific structures and mechanisms, such as fluorescence, aggregation, and non-specific chemical reactions. They recommend familiarizing researchers with common PAINS structures, checking the literature for known PAINS, and assessing assays to detect non-drug-like mechanisms. Despite occasional successful interactions, the authors emphasize that PAINS should be ignored, and academic drug discoverers must be more vigilant to avoid futile attempts.