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Small molecule effectors are essential for drug discovery. Specific molecular recognition, reversible binding and dose-dependency are usually key requirements to ensure utility of a novel chemical entity. However, artefactual frequent-hitter and assay interference compounds may divert lead optimization and screening programmes towards attrition-prone chemical matter. Colloidal aggregates are the prime source of false positive readouts, either through protein sequestration or protein-scaffold mimicry. Nevertheless, assessment of colloidal aggregation remains somewhat overlooked and under-appreciated. In this Review, we discuss the impact of aggregation in drug discovery by analysing select examples from the literature and publicly-available datasets. We also examine and comment on technologies used to experimentally identify these potentially problematic entities. We focus on evidence-based …