The human protamine gene cluster consists of three tightly regulated genes, protamine 1 (PRM1), protamine 2 (PRM2) and transition protein 2 (TNP2). Their products are required to repackage the paternal genome during spermiogenesis into a functional gamete. They reside within a single DNase I-sensitive domain associated with the sperm nuclear matrix, bounded by two haploid-specific Matrix Attachment Regions. The nuclear matrix is a dynamic proteinaceous network that is associated with both transcription and replication. While substantial effort has been directed toward pre- and post-transcriptional regulation, the role of the nuclear matrix in regulating haploid expressed genes has received comparatively little attention. In this regard, the functional organization of the human PRM1→PRM2→TNP2 cluster and where appropriate, comparisons to other model systems will be considered.