The purpose of this chapter is to give an overview of comorbidity and multimorbidity in patients with multiple long-term conditions, including those affecting the vascular system. Comorbidity is defined as having one or more additional long-term conditions in a patient who has an ‘index’ disease of prime interest. For example, a vascular disease such as coronary heart disease may be the index disease for a VAS specialist. Multimorbidity is defined as two or more long-term conditions within an individual, without any being seen as an index condition. For example, a family medicine doctor will have patients with multiple long-term conditions without anyone being more important than the other. Comorbidity and multimorbidity are rapidly rising due to ageing populations, and also widening health inequalities between patients of differing socioeconomic position. This chapter discusses issues of clinical complexity, including the relationship between mental and physical health conditions, effects of socioeconomic position, and challenges faced by patients and health care professionals when managing multiple long-term conditions. We focus on our work in this area from the United Kingdom (UK); however, much of what we present is applicable to other countries around the world. We reflect on the importance of generalism in the care of patients with comorbidity and multimorbidity, and the need for strong primary healthcare systems working with secondary care and other services in an integrated and collaborative way.