Chromosome cohesion is the term used to describe the cellular process in which sister chromatids are held together from the time of their replication until the time of separation at the metaphase to anaphase transition. In this capacity, chromosome cohesion, especially at centromeric regions, is essential for chromosome segregation. However, cohesion of noncentromeric DNA sequences has been shown to occur during double-strand break (DSB) repair and the transcriptional regulation of genes. Cohesion for the purposes of accurate chromosome segregation, DSB repair, and gene regulation are all achieved through a similar network of proteins, but cohesion for each purpose may be regulated differently. In this review, we focus on recent developments regarding the regulation of this multipurpose network for tying DNA sequences together. In particular, regulation via effectors and posttranslational modifications are reviewed. A picture is emerging in which complex regulatory networks are capable of differential regulation of cohesion in various contexts.