The paper presents the most recent advances in applications of alternative medium to replace polar aprotic solvents such as dimethylformamide (DMF), dimethylacetamide (DMAc) or N-methyl-2-pyrrolidone (NMP). Focus is made on the use of nonionic designer surfactant (e.g. TPGS-750-M) in water instead of traditional organic solvents. Much attention is given to its applications to several commonly used transformations in active pharmaceutical ingredient (API) synthesis, such as amidation reactions, Suzuki–Miyaura cross-couplings, nitro group reductions, and aromatic nucleophilic substitutions. Case studies of successful uses to attain improved green processes are included. Future directions and most recent results using tailor-made reagents suitable for micellar environments are given.