In the budding yeast Saccharomyces cerevisiae, synthetic lethality has been extensively used both to characterize interactions between genes previously identified as likely to be involved in similar processes as well as to uncover new interactions. We have performed a large study of the synthetic lethal interactions of the post-Golgi sec mutations. Included in this study are the interactions of the post-Golgi sec mutations with each other, with mutations affecting earlier stages of the secretory pathway, with selected mutations affecting the actin cytoskeleton, and with selected cell division cycle (cdc) mutations affecting processes thought to be important for or involving secretion, such as polarity establishment and cytokinesis. Synthetic negative interactions of the post-Golgi sec mutations appear (as predicted) to be largely stage specific, although there are some notable exceptions. The significance of these results is discussed in the context of both secretory pathway function and the utility of synthetic lethality studies and their interpretation.