In view of highly prevalent stressful conditions in modern working life, in particular increasing work pressure and job insecurity, it is of interest to know whether specific constellations of an adverse psychosocial work environment increase the risk of depressive disorder among employed people. This contribution gives a short overview of current research evidence based on an internationally established work stress model of effort-reward imbalance. Taken together, results from seven prospective epidemiological investigations demonstrate a two-fold elevated relative risk of incident depressive disorder over a mean observation period of 2.7 years among exposed versus non-exposed employees. Additional findings from experimental and quasi-experimental studies point to robust associations of effort-reward imbalance at work with proinflammatory cytokines and markers of reduced immune competence. These latter markers may indicate potential psychobiological pathways. In conclusion, incorporating this new knowledge into medical treatment and preventive efforts seems well justified.