Aminoglycosides are potent water-soluble antibiotics, with peak concentration-dependent bactericidal activity against many pathogenic aerobic Gram-negative bacilli and Staphylococcus aureus: they exhibit enduring antibacterial activity many hours after tissue concentrations become negligible and appreciation of this postantibiotic effect is leading to replacement of conventional multiple daily doses by large once-daily doses. Cotreatment with betalactams is commonly employed in order to exploit a synergism between these antimicrobial agents, particularly in severe Gram-negative sepsis. Resistance to aminoglycosides may be observed at several levels and is generally high when due to the acquisition of aminoglycoside modifying enzymes which may be plasmid-borne or transferred by transposable elements. Tobramycin is more effective than gentamicin and the other aminoglycosides against Pseudomonas aeruginosa and is less nephrotoxic than gentamicin. Higher serum tobramycin concentrations at the peak are associated with a longer postantibiotic effect and increased bactericidal activity. A longer dosage interval may decrease the risk of nephrotoxicity because higher transient serum aminoglycoside levels appear to be less nephrotoxic than lower but more persistent serum concentrations. Once-daily administration may also reduce the risk of ototoxicity through a similar mechanism. In a multicenter Italian study of 104 adult patients with severe bacterial lower respiratory tract infections, the safety and efficacy of a regimen of high dose, once-daily tobramycin alone or in combination with antipseudomonas betalactams was assessed. The overall bacteriological response was an elimination of the original pathogen in 70% of the patients while the clinical response mirrored the bacteriological results with a successful clinical outcome in 78% of patients. Adverse experiences were, in general, few and mild without oto- or nephrotoxicity. The once-daily, high dose regimen of tobramycin proved to be a safe and efficacious therapy for severe lower respiratory tract infections in adult patients.