Lamina-associated domains (LADs) are large genomic regions that interact with the nuclear lamina (NL) and help to guide the spatial folding of chromosomes in the interphase nucleus. LADs have been linked to gene repression and other functions. Recent studies have begun to uncover some of the molecular players that drive LAD–NL interactions. A picture emerges in which DNA sequence, chromatin components and nuclear lamina proteins play an important role. Complementary to this, imaging and single-cell genomics approaches have revealed that some LAD–NL interactions are variable from cell to cell, while others are very stable. Understanding LADs can provide a unique perspective into the general process of genome organization.