Potentially harmful disinfection by-products (DBPs) are formed upon drinking water treatment when disinfectants react with organic matter in the water. Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) provides information on the compositions of individual DBPs in the unknown, toxicologically relevant fraction, comprising non-volatile, high-molecular weight DBPs. This review evaluates current applications of FT-ICR-MS for DBP analysis to assist improved analysis with this technique. Four methodological aspects are in focus, 1) The use of quenching agents, 2) The choice of extraction method 3) The choice of ionization techniques/modes, and 4) Data processing including DBP formula verification and interpretation. Quenching can lead to decomposition or adduct formation and needs to be further evaluated or avoided. There is a large potential to expand FT-ICR-MS DBP analysis by applying different SPE sorbents and ionization techniques, and improved systematic verification procedures are important to ensure reliable non-target analysis.