Genome mining of natural product biosynthesis employs genome sequences to predict the biosynthetic potential of the producer strains guiding the purification and structure elucidation of novel compounds, and has been successfully applied in natural product discovery in both bacterial and fungal systems. In this review, the latest advances of genome mining of marine actinobacteria have been summarized, with emphasis on bioinformatic tools for sequence analysis and prediction of chemical structures, strategies for isolation of targeted natural products under the guidance of genome sequence information, activation of silent gene clusters and heterologous expression, as well as transcriptome mining developed by domestic scholars. Genome mining based on imaging mass spectrometry (IMS) was addressed as well. Although genome mining of marine actinobacteria has not been fully explored, we believe that genome mining will greatly facilitate natural product research in the near future not only in culturable marine actinobacteria, but also in mining of metagenomes in yet unculturable actinobacteria. We also propose that genome mining is not restricted in the identification of new structural and regulatory genes, and it is also important to discover and utilize various other genetic elements, including promoters with different strengths and sequences that response to various environmental conditions and signals, as well as small regulator RNA molecules.