Introduction: Muscle synergies have been proposed as a strategy employed by the central nervous system to control movements. Muscle synergy analysis is a well-established framework to examine the pathophysiological basis of neurological diseases and has been applied for analysis and assessment in clinical applications in the last decades, even if it has not yet been widely used in clinical diagnosis, rehabilitative treatment and interventions. Even if inconsistencies in the outputs among studies and lack of a normative pipeline including signal processing and synergy analysis limit the progress, common findings and results are identifiable as a basis for future research. Therefore, a literature review that summarizes methods and main findings of previous works on upper limb muscle synergies in clinical environment is needed to i) summarize the main findings so far, ii) highlight the barriers limiting their use in clinical applications, and iii) suggest future research directions needed for facilitating translation of experimental research to clinical scenarios. Methods: Articles in which muscle synergies were used to analyze and assess upper limb function in neurological impairments were reviewed. The literature research was conducted in Scopus, PubMed, and Web of Science. Experimental protocols (e.g., the aim of the study, number and type of participants, number and type of muscles, and tasks), methods (e.g., muscle synergy models and synergy extraction methods, signal processing methods), and the main findings of eligible studies were reported and discussed. Results: 383 articles were screened and 51 were selected, which involved a total of 13 diseases and 748 patients and 1155 participants. Each study investigated on average 15 ± 10 patients. Four to forty-one muscles were included in the muscle synergy analysis. Point-to-point reaching was the most used task. The preprocessing of EMG signals and algorithms for synergy extraction varied among studies, and non-negative matrix factorization was the most used method. Five EMG normalization methods and five methods for identifying the optimal number of synergies were used in the selected papers. Most of the studies report that analyses on synergy number, structure, and activations provide novel insights on the physiopathology of motor control that cannot be gained with standard clinical assessments, and suggest that muscle synergies may be useful to personalize therapies and to develop new therapeutic strategies. However, in the selected studies synergies were used only for assessment; different testing procedures were used and, in general, study-specific modifications of muscle synergies were observed; single session or longitudinal studies mainly aimed at assessing stroke (71% of the studies), even though other pathologies were also investigated. Synergy modifications were either study-specific or were not observed, with few analyses available for temporal coefficients. Thus, several barriers prevent wider adoption of muscle synergy analysis including a lack of standardized experimental protocols, signal processing procedures, and synergy extraction methods. A compromise in the design of the studies must be found to combine the systematicity of motor control studies and the feasibility of clinical studies. There are however several potential developments that might promote the use of muscle synergy analysis in clinical practice, including refined assessments based on synergistic approaches not allowed by other methods and the availability of novel models. Finally, neural substrates of muscle synergies are discussed, and possible future research directions are proposed. Conclusions: This review provides new perspectives about the challenges and open issues that need to be addressed in future work to achieve a better understanding of motor impairments and rehabilitative therapy using muscle synergies. These include the application of the methods on wider scales, standardization of procedures, inclusion of synergies in the clinical decisional process, assessment of temporal coefficients and temporal-based models, extensive work on the algorithms and understanding of the physio-pathological mechanisms of pathology, as well as the application and adaptation of synergy-based approaches to various rehabilitative scenarios for increasing the available evidence.