Fueled by CRISPR-Cas technology, a synergistic combination of advances in genomics, synthetic biology and bioinformatics have ushered in an era of genome-guided natural product discovery and engineering. As a versatile, programmable DNA targeting tool, CRISPR-Cas is increasingly employed to accelerate host and pathway engineering of actinomycetes, which are prolific producers of bioactive natural products. Here, we discuss the current state of the art, challenges and opportunities of CRISPR-Cas strategies to discover, diversify and improve the production of natural products from actinomycetes. Special emphasis is placed on the rapidly expanding CRISPR-Cas toolboxes for genome editing of non-Streptomyces actinomycetes.