Gaps in research focusing on work related stress, burnout, job satisfaction and general health of nurses is evident within developing contexts like South Africa. This study identified the relationship between work related stress, burnout, job satisfaction and general health of nurses. A total of 1200 nurses from four hospitals were invited to participate in this cross-sectional study (75% response rate). Participants completed five questionnaires and multiple linear regression analysis was used to determine significant relationships between variables. Staff issues are best associated with burnout as well as job satisfaction. Burnout explained the highest amount of variance in mental health of nurses. These are known to compromise productivity and performance, as well as affect the quality of patient care. Issues, such as security risks in the workplace, affect job satisfaction and health of nurses. Although this is more salient to developing contexts it is important in developing strategies and intervention programs towards improving nurse and patient related outcomes.