Communications Chemistry, Published online: 08 January 2026; doi:10.1038/s42004-025-01874-8Although ordered membrane nanodomains, also known as lipid rafts, have many proposed cellular functions, pharmacological tools to modulate protein affinity for rafts and to manipulate raft formation are currently lacking. Here, the authors screened 24,000 small molecules for compounds that impact the raft affinity of a known raft-preferring model protein, peripheral myelin protein 22 (PMP22), in giant plasma membrane vesicles, identifying three chemically distinct tools for modulating raft formation in a protein-independent manner by altering lipid–lipid interactions and membrane fluidity in biophysical experiments and in living cells.