For many years, the nuclear envelope was viewed as a passive barrier that separates the genetic material in the nucleus from the cytoplasm of the cell and permits regulated trafficking of various molecules through the nuclear pores. Research in the past two decades has shown that the nuclear envelope is a complex cellular compartment, which harbors tissue-specific resident proteins, extensively interacts with chromatin and contributes to spatial genome organization and regulation of gene expression. Chromatin at the nuclear periphery is organized into active and silenced domains punctuated by insulator elements. The nuclear envelope transmembrane proteins and the nuclear lamina serve as anchoring sites for heterochromatin. They recruit chromatin that has been modified with specific epigenetic marks, provide silencing factors that add new epigenetic modifications to genes located at the nuclear periphery, and sequester transcription factors away from the nuclear interior. On the other hand, proteins of the nuclear pores anchor as well as help generate active chromatin, promote transcription, and coordinate gene expression with mRNA export. The importance of these functions is underscored by aberrant distribution of peripheral chromatin and changes in gene expression that occur in cancer and heritable human diseases linked to mutations in nuclear envelope proteins. Although many mechanistic questions addressing the role of the nuclear envelope in genome organization and function have been answered in recent years, a great deal remains to be discovered in this exciting and rapidly moving field.