Researchers have found loneliness to play a role in gene activation and to be associated with psychiatric disorders such as depression and borderline personality disorder (e.g., 1,2). For research in this area to advance, it is now time to consider why this association has been found. In my commentary I would like to raise issues to be addressed in future research on loneliness and social neuroscience. A first issue to be addressed concerns the nature of loneliness. Researchers and theorists have made a distinction between loneliness and social isolation 3. Studies have indicated that some individuals may have large social networks and be involved in frequent social activities yet report being lonely. By contrast, other individuals may be socially isolated but not report feeling lonely. Loneliness appears to result from being dissatisfied with important aspects of relationships with others, such as the quality of the relationships or the lack of a particular type of relationship. Clearly, research needs to move beyond simply examining relationships between loneliness and the size of social networks or the frequency of social contacts. A second issue is the “pathologization” of loneliness. Loneliness is a common experience. For example, Cutrona 4 found that 75% of freshmen students at UCLA reported feeling lonely during their first two weeks on campus. By the spring quarter of their first year, only 25% of these students reported feeling lonely. As discussed by Weiss 5, other events such as divorce or the death of a spouse can create what he described as emotional loneliness. The research reviewed by Cacioppo et al 6 involves the effects of “chronic” loneliness (e.g., individuals who were found to be lonely over a three year period of time). It seems unlikely that loneliness experienced for a short period of time while making the transition to a new social setting (such as college) would result in such biological consequences as gene activation. At this point we do not know the necessary duration of loneliness for these consequences to occur, or whether overcoming loneliness through the formation of new or more satisfying relationships with others can prevent these negative effects of loneliness. A similar point should be made concerning the relationship between loneliness and psychiatric disorders like depression. Developing feelings of loneliness after moving to a new social setting is unlikely to lead to the development of clinical depression. However, the inability to overcome these feelings of loneliness through the development of new relationships with others may lead individuals moving to a new setting to become depressed. Understanding how the relationship between loneliness and depression changes over time is clearly of clinical importance. Another important issue for future research concerns whether or not chronic loneliness is the “cause” of such consequences as gene activation. Loneliness is associated with a number of other factors that could account for the associations that are described by Cacioppo et al. For example, personality characteristics such as extraversion and neuroticism are strongly related to loneliness 7; are these variables responsible for the association between loneliness and gene activation that has been found? Neuroticism may represent a “third variable” that is the cause of both loneliness and gene activation; if true, then we should find that the relationship between loneliness and gene activation becomes non-significant if we control for the effects of neuroticism on both of these variables. Similar issues arise concerning the relationship between loneliness and such psychiatric disorders as depression or borderline personality disorder. For example, do we find that loneliness is a predictor of developing clinical levels of depression because lonely individuals also tend to be high on neuroticism? It is time to move beyond examining the correlation between loneliness and neurological and psychiatric outcomes to the development and testing of theoretical models of these relationships. These models need to include factors that are hypothesized to determine feelings of loneliness, such as personality characteristics and the nature of people's relationships with others. The models should in turn specify how loneliness leads to such outcomes as gene activation and the development of psychiatric disorders such as depression or personality disorders. An important issue to consider involves whether or not loneliness serves as a mediator between characteristics of the individual (e.g., personality) and their social networks and these neurological and psychiatric disorders. As K. Lewin once commented 8, there is nothing so practical as a good theory; being able to ultimately intervene and prevent these negative effects of loneliness may depend upon our ability to understand and alter its causes.