Microbial natural products have been for decades one of the most successful sources of drugs to treat infectious diseases. The high occurrence of resistances to all major classes of known antibiotics represents today a new challenge and new classes of antibacterial compounds are urgently needed to respond to this unmet clinical need. While natural products discovery programs have been gradually abandoned by big pharma, smaller biotechnology companies and other research organizations are taking the lead in the discovery of novel antibacterials. A survey of recent patents has shown that in spite of the efforts, few novel compounds are being developed that can overcome most of the emerging multi-resistant and pan-resistant pathogens. In order to respond to the current challenges of discovering novel antibiotics, new approaches are required to be developed to further exploit the microbial resources and their biosynthetic potential as an untapped source of novel metabolites. Strategies to mine microbial collections for orphan biosynthetic pathways and novel species thought to be uncultivable, are emerging as a need within antibacterial drug discovery programs, in combination with high throughput screening and chemical dereplication of novel compounds. Different innovative methods that are being developed to respond to the new challenges that are faced today by drug discovery programs will ensure the evolution of these strategies into a completely new framework that will address the renovated interest in the discovery of novel classes of antibiotics.