Large clinical trials have demonstrated that new oral anticoagulants (NOACs) are at least as efficient as vitamin K antagonists (VKAs) in preventing thromboembolic events, while providing a better safety profile. The relatively stable pharmacokinetics and pharmacodynamics, the reduced reports on food and drug interactions, and the wide therapeutic windows of NOACs appear to provide a more predictable anticoagulant effect than that observed with VKAs, enabling the use of fixed doses without the need for monitoring. However, the safe implementation of NOACs may require additional judgment, and one should not have the erroneous impression that NOACs are free from interactions or that inter- and intra-individual variability is absent with NOACs. In fact, a consensus seems to have been reached concerning the usefulness of “circumstantial” testing in certain clinical scenarios. Recent data also suggest that factors such as intercurrent diseases, drug interactions, and inexplicable variability may occasionally alter the anticoagulant effect of NOACs. Furthermore, the issue of nonadherence, already high in VKA-treated patients, may represent an even greater clinical concern with NOACs, given their short half-lives. This review aims to underline the main arguments that support the need for NOAC monitoring, at least in selected categories of patients. Additionally, an overview of classic coagulation assays and novel laboratory techniques that may provide a tool for NOAC monitoring is also provided.