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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 PRM1PRM2TNP2 cluster and where appropriate, comparisons to other model systems will be considered.