<p>Organic fluorescent dyes are indispensable tools in bioimaging; however, their translational viability increasingly depends on pharmacokinetic performance rather than optical brightness alone. For systemically administered small-molecule dyes, the dominant elimination route, renal versus hepatobiliary, is largely encoded by a compact set of structural and physicochemical variables that can be deliberately programmed during the synthetic stage. This review presents a chemical design framework for controlling clearance by examining four interconnected determinants: (i) the serum state of the dye, governed by protein binding and aggregation propensity, which defines effective hydrodynamic behavior in circulation; (ii) charge distribution and charge topology, which regulate the hydration shell and nonspecific adsorption to biological surfaces; (iii) lipophilicity and solvent-exposed aromatic surface area, which bias hepatic uptake and biliary processing; and (iv) scaffold stability and susceptibility to biotransformation, which determine whether dyes are eliminated intact or as polar metabolites. Practical structure–clearance design rules and emerging opportunities in data-driven clearance prediction and standardized pharmacokinetic reporting are discussed to accelerate the rational development of clearance-tunable imaging agents for clinical use.</p>