The study proposes that loop extrusion is the mechanism underlying the formation of Topologically Associating Domains (TADs) in human interphase chromosomes. Loop extrusion involves cis-acting loop-extruding factors (LEFs), likely cohesins, which form progressively larger loops. These loops are stalled at TAD boundaries by boundary proteins, including CTCF. Polymer simulations show that this model produces TADs and other features of Hi-C data. Each TAD consists of multiple dynamically formed loops rather than a single static loop. Loop extrusion explains experimental observations such as the preferential orientation of CTCF motifs, enrichments of architectural proteins at TAD boundaries, and boundary deletion experiments. It also predicts specific effects on CTCF and cohesin depletion. Loop extrusion has broader implications for processes like enhancer-promoter interactions, orientation-specific chromosomal looping, and mitotic chromosome compaction. The study highlights that TADs are not stable loops but dynamic structures formed by loop extrusion. CTCF and cohesin play key roles as boundary elements and loop-extruding factors, respectively. The model predicts effects of cohesin and CTCF perturbations on chromosomal organization and supports the idea that TADs emerge as population-average features. The findings suggest that loop extrusion is a fundamental mechanism for chromosomal organization in interphase.The study proposes that loop extrusion is the mechanism underlying the formation of Topologically Associating Domains (TADs) in human interphase chromosomes. Loop extrusion involves cis-acting loop-extruding factors (LEFs), likely cohesins, which form progressively larger loops. These loops are stalled at TAD boundaries by boundary proteins, including CTCF. Polymer simulations show that this model produces TADs and other features of Hi-C data. Each TAD consists of multiple dynamically formed loops rather than a single static loop. Loop extrusion explains experimental observations such as the preferential orientation of CTCF motifs, enrichments of architectural proteins at TAD boundaries, and boundary deletion experiments. It also predicts specific effects on CTCF and cohesin depletion. Loop extrusion has broader implications for processes like enhancer-promoter interactions, orientation-specific chromosomal looping, and mitotic chromosome compaction. The study highlights that TADs are not stable loops but dynamic structures formed by loop extrusion. CTCF and cohesin play key roles as boundary elements and loop-extruding factors, respectively. The model predicts effects of cohesin and CTCF perturbations on chromosomal organization and supports the idea that TADs emerge as population-average features. The findings suggest that loop extrusion is a fundamental mechanism for chromosomal organization in interphase.