The proteome adapts to multiple situations occurring along the life of the cell. To face these continuous changes, the cell uses posttranslational modifications (PTMs) to control the localization, association with multiple partners, stability, and activity of protein targets. One of the most dynamic protein involved in PTMs is Ubiquitin (Ub). Together with other members of the same family, known as Ubiquitin-like (UbL) proteins, Ub rebuilds the architecture of a protein in a few minutes to change its properties in a very efficient way. This capacity of Ub and UbL is in part due to their potential to form complex architectures when attached to target proteins or when forming Ub chains. The highly dynamic formation and remodeling of Ub chains is regulated by the action of conjugating and deconjugating enzymes that determine, in due time, the correct chain architecture for a particular cellular function. Chain remodeling occurs in response to physiologic stimuli but also in pathologic situations. Here, we illustrate well-documented cases of chain remodeling during DNA repair, activation of the NF-κB pathway and autophagy, as examples of this dynamic regulation. The crucial role of enzymes and cofactors regulating chain remodeling is discussed.