Central venous access is a paramount part of the clinical current practice in a growing number of clinical specialties. Their full knowledge and management are requested by a relevant number of health experts, and consequently, even the more challenging circumstances should be faced with a pertinent knowledge. In this chapter, coagulopathy and anticoagulation treatments will be analyzed as possible risk carrier situations, air embolism and cardiac perforation will be described as possible complications, and suggestions will be provided about difficult or failed repeated access. The common thread that will be often recalled for those different clinical scenarios, will be the risk benefit balance. If coagulopathy and anticoagulation could be partially amended with medical treatments, complications such as air embolism and cardiac perforations can be challenging as well as decide how much is worth to keep trying in case of cannulation failing. Therefore even with a full technical knowledge and a complete skill set, the clinical setup must always be considered for a thoughtful management of the patient itself no matter how important the venous access could be. Another important issue examined will be imaging guidance. For the listed topic, ultrasound and fluoroscopic guidance can make the real difference with a significant impact on cannulation outcome. This specific technical element will be often considered in the chapter with a special focus when possible on pros and cons. Finally for each paragraph, a list of practical suggestion will be provided when possible.