Sepsis is recognized by the presence of physiologic and laboratory changes that reflect the inflammatory response to infection on cellular and systemic levels. Comorbid conditions, such as cirrhosis, end-stage renal disease, and obesity, alter patients’ susceptibility to infection and their response to it once present. Baseline changes in vital signs and chronic medications often mask clues to the severity of illness. The physiologic, hematologic, and biochemical adjustments that accompany pregnancy and the puerperium introduce similar challenges. Emergency providers must remain vigilant for subtle alterations in the expected baseline for these conditions to arrive at appropriate management decisions.