Decision-making is regulated by many associated brain regions, including the locus coeruleus (LC) and the prefrontal cortex (PFC). Disruptions in decision-making are a key feature of many disorders including attention-deficit/hyperactivity disorder which is disproportionately diagnosed in one sex over another for reasons unknown. LC or its primary neurotransmitter norepinephrine (NE) have been implicated in the etiology or treatment of disrupted decision-making. Understanding the relationship among LC, PFC, and decision-making across sexes may provide insight into the basic neurobiology of cognition and disorders that lead to disrupted decision making. There are sex differences in LC anatomy, however studies investigating sex differences in LC-PFC regulation of decision-making are limited. This dissertation aims to investigate key substrates in the LC-PFC system underlying decision-making in females and males. As similar sex differences have been observed in behavior and anatomy of human and rodent LCs, the following experiments were conducted in Long-Evans rats: Chapter 2 objective: Determine the decision-making effect of increased LC activity, with additional study of impact on motivation and reward consumption as control behaviors. This was tested by administering excitatory chemogenetics into the LCs before performance of the two-alternative forced choice (2AFC) decision-making task. Results indicated that females were more sensitive to increases to LC activity than males. Chapter 3 objective: Assess behavioral effects of NE activity. This was tested by administering atomoxetine systemically before 2AFC performance. Results indicated that males were more sensitive to increases to NE availability than females. This chapter further assessed the influence of adrenergic receptors on decision-making. This was tested by administering propranolol systemically before 2AFC performance. Results indicated that both females and males were similarly sensitive to decreases to NE receptor availability. Chapter 4 objective: Compare NE projections to the PFC. This was tested by comparing density of NE projections to the PFC, density of NE release sites in the PFC, and cell-type distribution of RNA coding for NE receptors in the PFC. Results indicated that NE projections and release sites in the PFC were similar in females and males. However, β1 receptor RNA had higher expression on glutamatergic neurons in females, and β2 in males.