Catheter-related bloodstream infections (CBIs) rank among the most frequent and potentially lethal nosocomial infections. Intravascular devices become contaminated on the outer surface during nonaseptic insertion or maintenance of the catheter exit site or endoluminally during hub manipulation. CBI is heralded by spiking fever, malaise and rigors and should be promptly diagnosed to prevent endocarditis and septic metastasis. In about two-thirds of the cases the offending organisms are coagulase-negative staphylococci; Staphylococcus aureus, gram-negative bacilli, and Candida sp. are responsible for one-third of these infections and carry a worse prognosis. Diagnosis of CBI relies on proper bacteriologic techniques, some of which can be performed in situ avoiding withdrawal of the device. Prevention strategies should aim at avoiding extra- and endoluminal contamination and should be based on three main pillars: maximal aseptic barriers at insertion, appropriate site maintenance, and junctional (hub) care and protection. Treatment includes catheter withdrawal and appropriate antibiotic coverage. For long-term cuffed catheters, local treatment with intraluminal administration of antibiotics is effective and can save a significant number of catheters, particularly those colonized by coagulase-negative staphylococci.