Three terms are commonly used interchangeably to identify vulnerable older adults: comorbidity, or multiple chronic conditions, frailty, and disability. However, in geriatric medicine, there is a growing consensus that these are distinct clinical entities that are causally related. Each, individually, occurs frequently and has high import clinically. This article provides a narrative review of current understanding of the definitions and distinguishing characteristics of each of these conditions, including their clinical relevance and distinct prevention and therapeutic issues, and how they are related. Review of the current state of published knowledge is supplemented by targeted analyses in selected areas where no current published data exists. Overall, the goal of this article is to provide a basis for distinguishing between these three important clinical conditions in older adults and showing how use of separate, distinct definitions of each can improve our understanding of the problems affecting older patients and lead to development of improved strategies for diagnosis, care, research, and medical education in this area.