Updated project metadata. In proteomics, the changes occurring in cellular proteomes upon drug treatment are used to identify the drug targets and the mechanism of action. However, proteomes of cultured cells undergo also natural alteration associated with changes in the media, attaining a degree of confluence as well as due to cell division, metabolic and circadian cycles. These changes are implicitly assumed to be minimal. In this study, we tested this assumption experimentally by comparing the proteome dynamics of untreated HCT116 and A375 cancer cells during 48 h. Time series revealed considerable growth-related proteome changes. The magnitude of these variations reveals an unexpected plasticity of the cellular proteome and reinforces the need, generally accepted in theory but not always followed in practice, to use a time-matched control when measuring drug-induced proteome changes.