Comorbidity presents significant problems to investigators engaged in the search for biomarkers of post-traumatic stress disorder (PTSD) because it means that multiple overlapping psychiatric phenotypes may be present in any PTSD sample. This chapter reviews research on an internalizing/externalizing model of post-traumatic psychopathology and discusses its relevance to the search for PTSD biomarkers. It focuses on two candidate biomarkers that have been studied extensively in relation to PTSD—basal cortisol level and startle reflex amplitude—but have yielded complicated and mixed results. Our review of the cortisol literature finds evidence for links between disorders of the internalizing spectrum and elevated levels of cortisol and links between externalizing psychopathology and low levels of cortisol. The review of the startle reflex literature reveals an association between exaggerated startle and fear-related disorders of the internalizing spectrum. These findings illustrate how individual differences in internalizing and externalizing comorbidity may moderate associations between these measures and PTSD diagnostic status. The chapter concludes with a discussion of the advantages of studying latent dimensions of comorbidity in future PTSD biomarker research.