In the sea, there are many resources and novel chemical entities with biological activities that may be useful for finding drugs with greater efficacy and specificity to treat a variety of human diseases. Although there are some reports on promising natural products to date, the technology on small-molecule-based methods to isolate protein sets using a proteomic approach, which is currently useful for pharmaceuticals, is lacking. The separation of proteins from marine organisms, especially calcifying marine organisms, which are part of one of the most biologically diverse and ecologically important ecosystems on the planet, is difficult due to contamination by skeletal tissues and the high sensitivity of tissues to handling. Here, I highlight some recent studies of marine organisms, paying particular attention to their discovery, medicinal activities, and mechanisms of action. In addition, I discuss an effective protocol from sample preparation to protein purification for proteomic analysis to isolate candidate proteins for target identification, helping turn the current wealth of proteomic information into drug discovery and optimization. This information might be useful for medicinal chemists, biologists and biotechnologists for further studies utilizing the great resources of these promising marine organisms.