- The following manuscript is mainly conceptual in nature. It should be read with reservation since the relevance of its suggestions have yet to be proven. Basically it proposes two rules for the differentiation between primary illness‐related pathophysiological vs. secondary adaptational processes. These rules may guide hypotheses generation for further research that is aimed at understanding psychiatric disorders and their shared and unshared mechanisms. For example, in the case of anxiety disorders and depression, it may be of interest to learn if their shared properties are of primary pathophysiological or secondary adaptational significance. We first present some historical observations on the development of the concept of “secondary adaptational processes.” We assume such adaptational processes are generated by the organism in order to compensate for primary pathophysiological malfunction or impairment. Next, we propose rules that may enable the dissection of secondary adaptational from primary pathophysiological processes. We also discuss the possible implications of designing studies to sort out these processes, suggesting that the understanding of adaptational processes, may explain the effects of “placebo treatment.” Finally we illustrate the application of these rules by two examples: a) amygdala activation, a biological alteration shared by anxiety disorders and major depression and b) elevated plasma soluble interleukin 2 receptor, an unshared property by anxiety disorders and major depression. Also, the first example relates to a biological perturbation associated with a primary pathophysiological mechanism, while the second represents a biological alteration associated with secondary adaptational processes. Depression and Anxiety 14:105–111, 2001. © 2001 Wiley‐Liss, Inc.