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Medical chemists use a wide variety of biochemical and cellular assays to direct compound optimization. Structure-Activity Relationship (SAR) campaign decisions are influenced by the information gathered from these tests. As a result, it is crucial for medicinal chemists to comprehend both the advantages and disadvantages of each assay used to evaluate produced analogs. We argue that early collaboration between assay biologists, informaticians, and medicinal chemists is essential for the successful execution of a medicinal chemistry campaign, their combined skill sets are essential for not only creating reliable assays but also for implementing a successful screening cascade in which numerous orthogonal and counter assays are chosen to confirm the activity and target(s) of the synthesized compounds. We examine various instances of drug and chemical probe discovery from joint National Center for Advancing Translational Sciences/National Institutes of Health projects and scientific literature where the evaluation of substances in secondary or orthogonal assays resulted in the discovery of unexpected activities, compelling a reevaluation of the original assay design that was used to discover the biological activity of the compound. The objective of this Perspective is to steer toward the creation of physiologically appropriate assays that may accurately capture the genuine bioactivity of compounds being generated in a medicinal chemistry campaign using these retrospective case studies.