Small molecules and drugs are not homogenously distributed across cells, and are instead enriched in distinct subcellular compartments and membraneless biomolecular condensates. A new study lays out the path to identifying chemical features or ‘rationales’ that confer condensate-selective partitioning of small molecules.

Like dew in the morning mist or droplets of oil dispersed in water, some biomolecules undergo phase transition to form membraneless condensates within living cells1,2. Akin to oil droplets in water, the internal physicochemical properties within a biomolecular condensate can differ markedly from the surrounding cellular milieu. Moreover, condensates formed by different collections of biomolecules (such as proteins, nucleic acids or metabolites) can also differ from each other. As may be expected, condensates containing distinct sets of biomolecules are implicated in distinct cellular functions. It follows that formation of aberrant condensates or loss of functional condensates would contribute to the etiology of various diseases, including neurodegeneration, cancer and viral infection. With the growing appreciation for the pervasive roles of condensates in cellular function, elucidating the physical principles that govern their formation has become an active area of scientific investigation3. The recent observation that several widely prescribed chemotherapeutic agents selectively partition into distinct condensates where they mediate their actions has captured the attention of scientists in academia and birthed new biotech companies4,5. Deciphering the ‘chemical grammar’ that guides the selective partitioning of small molecules into distinct biomolecular condensates is an emerging frontier that will lead to the next generation of therapies. In this issue, Kilgore et al.6 take an important step towards identifying the chemical features — or rationales— that correlate with the ability to selectively partition into distinct condensates6.