Lipophilicity (octanol-water partition coefficient) is a very important property that is of equal importance as bioactivity in the context of drug development. The lipophilicity parameter is relevant as a measure for membrane permeability, as well as for hydrophobic desolvation (unselective binding). Nowadays, the guidance for optimal lipophilicity has progressed from ‘optimal value ranges’ (eg as in the Lipinski rules) to more modern metrics such as ligand lipophilic efficiency (bioactivity per unit of lipophilicity).1 Essentially, the goal is to achieve minimal lipophilicity as allowed by membrane permeability.2 This means it is important to understand how structural changes affect lipophilicity. Fluorination is widely recognised for its impact on molecular lipophilicity. In contrast to aromatic fluorination, the impact of aliphatic fluorination on lipophilicity is very substratedependent, and the underlying mechanisms are the subject of intense investigations, including by our research group.3 As introduction of this presentation, we will share some new insights on how the interplay between trifluoromethylation and heteroatoms (primarily oxygen) can profoundly affect lipophilicity. Our group also asked the question whether lipophilicity changes caused by fluorination are actually also modifying membrane partitioning. In this presentation, we will discuss how the influence of fluorination on molecular lipophilicity correlates with membrane partitioning.4 The results suggest a promising new avenue in lipophilicity optimisation. The presentation will contain an organic chemistry element (the synthesis of fluorinated model compounds as well as analogues of a number of drugs), as well as a discussion of lipophilicity and membrane partitioning.