Chronic diseases can severely impair patients' quality of life but little information is available about the long-term impact of chronic diseases. The chronic nature of disease may decrease patients' psychosocial well-being, may change their attitude towards life goals and influence major life-changing decisions (MLCDs). Understanding of the impact on MLCDs is largely missing from health outcomes research. It is potentially important in the assessment of the overall burden and cumulative impact of chronic disease. This chapter reviews the concepts of life events, life transition, life goals concepts and what constitutes a long-term impact, essential background to this area. We also describe the relationship of the concept of MLCD with the concept of cumulative life course impairment. Chronic disease has long-term impact on patients' lives, particularly by influencing MLCDs related to career, job, relationships, education, having children and early retirement. We describe qualitative research carried out in Cardiff that has sought to give more detailed insight into what decisions constitute MLCDs, in patients both from dermatology and from several general medical disciplines. We have also proposed the MLCD Profile to measure the number of MLCDs that an individual patient may have experienced as being influenced by chronic disease. Adding the domain of MLCDs to how we think about the burden of disease experienced by an individual, could broaden understanding of the true extent of disease impact.