The introduction of ultrasound guidance over the last two decades brought progress, new blocks and new challenges to Regional Anesthesia. This narrative review addresses and discusses facts, frequent questions, beliefs, controversies, unsolved issues, open safety questions and existing knowledge gaps related to efficacy and safety of ultrasound guided regional anesthesia (USGRA), based on the available literature. We discuss evidence-based advantages and limitations of ultrasound guidance, as well as unresolved questions, with respect to successful anesthesia, undesired side effects and patient safety, like nerve injury and local anesthetic systemic toxicity (LAST). In an educational approach we also emphasize some practical aspects of our everyday experience as well as necessary structural requirements.