Overuse of broad-spectrum antibiotics to control human and plant pathogens greatly accelerated the development of antibiotic resistance among bacteria and fungi. Therefore, usage of new approaches is necessary to control outbreaks of phytopathogenic diseases as well as multidrug-resistant human pathogens. Many of the polyketides (PKs) and lipopetides (LPs) produced by Bacillus and Paenibacillus species have been described as antimicrobial agents that can be potentially applied as sustainable bio-organic products in medicine against human pathogens and in agriculture for controlling plant pathogens. The present review provides a general information about the classification and biochemical structure of known Bacillus- and Paenibacillus-secreted PKs, as well as ribosomally and nonribosomally synthesized peptides, their functional features, gene clusters involved in their production, and the mode of action of these metabolites.