Background: Work-related psychosocial stress can cause mental and physical illnesses resulting in high costs for the individual, the economy and society. Small and medium-sized enterprises (SMEs) employ the majority of the world’s workforce and often have fewer financial and human resources compared to larger businesses. The aim of this review is to summarize current knowledge on work-related stress in SMEs according to well-established guidelines categorizing psychosocial factors at work. Methods: A systematic database search was carried out in PubMed, PsycINFO, PSYNDEX and Business Source Premiere from March to June 2019, updated in January 2020. Data of included studies were analyzed and mapped into five themes: “work content and task”, “organization of work”, “social relations”, “working environment” and “new forms of work”. Results: After full-text screening, 45 out of 116 studies were included for data extraction. Studies were very heterogeneous and of varying quality, mostly applying a cross-sectional study design. Psychosocial factors in SMEs have been researched with a focus on the work patterns “work organization” and “work content and task”. Conclusions: This review underlines the need for more and better quality research of psychosocial factors in SMEs, particularly in relation to ongoing and new challenges in the workplace, including stressors related to the process of digitalization or the development of safe working conditions during the emerge of new infectious diseases.