An advanced understanding of the pathogenesis of psoriasis has led to the development of multiple therapeutic options for moderate-to-severe psoriasis. Tumor necrosis factor inhibitors, ustekinumab, interleukin-17 inhibitors, and guselkumab (an interleukin-23 inhibitor recently approved for psoriasis) are commercially available biologic agents for psoriasis. Evidence from clinical trials provides pertinent information regarding the safety and efficacy of biologic agents for psoriasis, which should be integrated into clinical decision making. However, disease presentations, disease severity, and comorbid conditions can complicate the choice of initial treatment, which underscores the importance of providing personalized therapy for patients with psoriasis. Furthermore, each biologic agent offers unique benefits and limitations for the treatment of patients with psoriasis. Here, evidence-based recommendations are presented and discussed regarding first-line biologic therapy options for patients with psoriasis and distinct comorbid conditions or patient-related factors. We discuss the comorbid conditions of psoriatic arthritis, multiple sclerosis, congestive heart failure, inflammatory bowel disease, hepatitis B, and latent tuberculosis. Moreover, we describe treatment recommendations for distinct patient populations with psoriasis, including pediatric patients with psoriasis and patients with psoriasis of childbearing potential and nursing.