The study investigates the genetic and physiological mechanisms underlying heteroresistance, a clinically significant phenotype where small populations of antibiotic-resistant bacteria coexist within a predominantly susceptible population. The researchers focused on a multi-resistant *Klebsiella pneumoniae* isolate and identified three primary drivers of gene dosage-dependent heteroresistance: tandem amplification, increased plasmid copy number, and transposition of resistance genes onto cryptic plasmids. These mechanisms impose fitness costs and are genetically unstable, leading to rapid reversion to susceptibility in the absence of antibiotics. Using a mouse gut colonization model, the authors demonstrated that elevated resistance-gene dosage can result in antibiotic treatment failures. Additionally, they found that these mechanisms are prevalent among *Escherichia coli* bloodstream isolates. The findings highlight the need for treatment strategies that address the complex interplay between plasmids, resistance cassettes, and transposons in bacterial populations, emphasizing the challenges in detecting and treating heteroresistant bacteria.The study investigates the genetic and physiological mechanisms underlying heteroresistance, a clinically significant phenotype where small populations of antibiotic-resistant bacteria coexist within a predominantly susceptible population. The researchers focused on a multi-resistant *Klebsiella pneumoniae* isolate and identified three primary drivers of gene dosage-dependent heteroresistance: tandem amplification, increased plasmid copy number, and transposition of resistance genes onto cryptic plasmids. These mechanisms impose fitness costs and are genetically unstable, leading to rapid reversion to susceptibility in the absence of antibiotics. Using a mouse gut colonization model, the authors demonstrated that elevated resistance-gene dosage can result in antibiotic treatment failures. Additionally, they found that these mechanisms are prevalent among *Escherichia coli* bloodstream isolates. The findings highlight the need for treatment strategies that address the complex interplay between plasmids, resistance cassettes, and transposons in bacterial populations, emphasizing the challenges in detecting and treating heteroresistant bacteria.