The objective measurement of fatigue is of critical relevance in areas such as occupational health and safety as fatigue impairs cognitive and motor performance, thus reducing productivity and increasing the risk of injury. Wearable systems represent highly promising solutions for fatigue monitoring as they enable continuous, long-term monitoring of biomedical signals in unattended settings, with the required comfort and non-intrusiveness. This is a p rerequisite for the development of accurate models for fatigue monitoring in real-time. However, monitoring fatigue through wearable devices imposes unique challenges. To provide an overview of the current state-of-the-art in monitoring variables associated with fatigue via wearables and to detect potential gaps and pitfalls in current knowledge, a systematic review was performed. The Scopus and PubMed databases were searched for articles published in English since 2015, having the terms “fatigue,” “drowsiness,” “vigilance,” or “alertness” in the title, and proposing wearable device-based systems for non-invasive fatigue quantification. Of the 612 retrieved articles, 60 satisfied the inclusion criteria. Included studies were mainly of short duration and conducted in laboratory settings. In general, researchers developed fatigue models based on motion (MOT), electroencephalogram (EEG), photoplethysmogram (PPG), electrocardiogram (ECG), galvanic skin response (GSR), electromyogram (EMG), skin temperature (Tsk), eye movement (EYE), and respiratory (RES) data acquired by wearable devices available in the market. Supervised machine learning models, and more specifically, binary classification models, are predominant among the proposed fatigue quantification approaches. These models were considered to perform very well in detecting fatigue, however, little effort was made to ensure the use of high-quality data during model development. Together, the findings of this review reveal that methodological limitations have hindered the generalizability and real-world applicability of most of the proposed fatigue models. Considerably more work is needed to fully explore the potential of wearables for fatigue quantification as well as to better understand the relationship between fatigue and changes in physiological variables.