Marine macro- and micro-biota offer a wealth of chemically diverse compounds that have been evolutionary preselected to modulate biochemical pathways. Many industrial and academic groups are accessing this source using advanced technology platforms. The previous edition of this chapter offered some practical guidance in the process of extraction and isolation of marine natural products with more emphasis on the procedures adapted to the physical and chemical characteristics of the isolated compounds. Automation and direct integration of the isolation technology into high-throughput screening (HTS) systems were also reported. In this edition, we refer to some new topics which are heavily represented in the literature. These include methods for sampling the deep ocean and the procedures for culturing high-pressure-adapted (piezophilic) marine microorganisms to be amenable to laboratory investigation. A brief discussion on genomic-guided approaches to detect the presence of biosynthetic loci even those that are silent or cryptic is also included.