This paper combines theoretical considerations with experimental evidence to explain the behavior of cellulose when exposed to different media. The observations are explained based on the amphiphilic character of the cellulose molecule and fundamental physicochemical phenomena. Nanofibrillated cellulose was chosen to demonstrate the phenomena since due to its high surface area the effects at issue are pronounced. X-Ray photoelectron spectroscopy and contact angle measurements were used to demonstrate the chemical and energetical changes taking place on the cellulose surface, and atomic force microscopy was used to follow nanoscale structural changes. Due to its hydrophilicity cellulose is well dispersed in water. However, when exposed to non-polar media like air or organic solvents cellulose undergoes partly irreversible reorganization like aggregation or surface passivation in order to find the energetically most favorable state. We show that when NFC is dried directly from water it aggregates strongly and accumulates a very high amount of non-cellulosic material on the surface. Very similar effects also occur when using non-polar media like toluene. Hence, both the reactivity and nanoscale structure are lost. In contrast, NFC retains its reactivity and nano-scaled structure in amphiphilic media like dimethyl acetamide as is confirmed with a simple silylation reaction. We conclude that the interfacial phenomenon is general for cellulosic material but has the most practical impact on applications of nanoscaled cellulose or ultrathin cellulose films.