Many concepts and guidelines in medicinal chemistry have been introduced to aid in successful drug discovery and development. An example is the concept of Pan-Assay Interference Compounds (PAINS) and the elimination of such nuisance compounds from high-throughput screening (HTS) libraries. PAINs, along with other guidelines in medicinal chemistry, are like double-edged swords. If used appropriately, they may be beneficial for drug discovery and development. However, rigid and blind use of such concepts can hinder productivity. In this perspective, we introduce GAINS (give attention to limitations in assays) and highlight its relevance for successful drug discovery.