Undoubtedly, during the next decades many onshore pipelines are expected to be constructed worldwide. Depending on the local site conditions, the hazard of slope instability and the associated risk to a pipeline are certainly very important issues of pipeline design. Nevertheless, in areas characterized by moderate or high seismicity slope instability assessment and treatment are much more demanding and challenging as many issues are directly or indirectly associated to a potential earthquake. Strong ground shaking during a seismic event and nonlinear ground response may cause a slope failure that will certainly impose permanent ground deformations (PGDs) to the pipeline, and consequently additional pipeline distress. The current paper aims to illustrate the main topics of seismic slope instability that have to be coped with for the optimum design of onshore pipelines. The first part of the paper is devoted to seismic slope instability assessment. After a short overview of some basic concepts, the available methods of seismic slope stability assessment are briefly described. The second part of the paper refers to the possible mitigation measures that may be analyzed and designed for slope stabilization and minimization of PGDs, while the third part deals with the issue of “soil-pipeline interaction” due to the PGDs potentially caused by an earthquake (without - or even with - the stabilization measures) and the concept of “strain-based design”. Finally, the paper deals with the provisions of european seismic norm (i.e. EN1998) related to slope stability, retaining structures, and onshore pipelines, which are rather insufficient to cover fully the aforementioned issues. Through characteristic case studies, it is shown that, apart from reliable data and advanced numerical modelling, engineering judgment is also required to obtain a realistic quantitative assessment and to design the optimum (i.e. safe and cost-effective) mitigation measures.