We analyzed the consistency, or lack thereof, of the conjectured connection between the sign of Jones−Dole's Bcoefficient, or its isobaric-temperature derivative, and the structure-making/breaking ability of a solute in a dilute solution. We sought to shed light on some crucial issues, including (i) whether Jones−Dole's B-coefficient contains any embedded microstructural information, (ii) whether we can either assign any definite foundation to the widely used assumption about the sign of the Bcoefficient and its structure-making/breaking trend or provide a rational justification for its use as a structure-making/breaking marker, and (iii) whether we actually need Jones−Dole's B-coefficient and its isobaric-temperature derivative as markers for the interpretation of structure-making/breaking trends. Thus, we first addressed the fundamental (statistical mechanical) microscopic to (thermodynamic) macroscopic foundations of a rigorous approach to the structure-making/breaking ability of a solute, regardless of the type of solvent or nature of the solute−solvent intermolecular interaction asymmetries, and its exact relationships to the resulting solution thermodynamics. Then, we derived the required conditions for the signs of the B-coefficient and/or its isobaric-temperature derivative to describe either a structure-making or a structure-breaking event, according to the actual solute-induced perturbation of the solvent microstructure, and consequently, tested the rationale underlying the B-based conjectured structure-making/breaking markers. Moreover, we invoked a well-known transition-state (TS) interpretation of the B-coefficient to connect it explicitly to the derived molecular-based structure-making/breaking signature and to find under which TS conditions the signs of the B-coefficient and its temperature derivative could describe the actual solute-induced perturbation of the solvent microstructure. We illustrated the actual structure-making/breaking behavior for a series of aqueous solutes over a wide range of solute−solvent intermolecular interaction asymmetries and compared their behavior against that predicted by Jones−Dole's based markers. This comparison, supported by rigorous thermodynamic arguments, highlighted the lack of uniqueness (or one-to-one correspondence) in the response of the B-based markers to the solute−solvent intermolecular interaction asymmetry, and therefore, their inadequacy as structure-making/breaking descriptors. Finally, we discuss the findings and provide a cautionary outlook on the use of the viscositybased structural markers.