Psoriasis is a common immune-mediated chronic skin disease. Disease severity is influenced by several factors including the extent and localization of skin lesions, severity of pruritus and comorbidities, such as psoriatic arthritis. Moderate to severe psoriasis is defined when cutaneous involvement is diffuse, covering more than 10% of the body surface areas and/or involving the sensitive areas such as face, genitalia, folds or nails or has high impact on patients' quality of life, and it occurs in approximately 15% of cases. In recent years, a growing understanding of psoriasis pathophysiology allowed the development of an increasing number of effective and safe treatments, including biologicals that are indicated for moderate to severe psoriasis. Different classes of biologicals have been already approved, including TNF-α (etanercept, infliximab, adalimumab and certolizumab pegol), IL-12/23 (ustekinumab), IL-17 (secukinumab, ixekizumab, brodalumab) and IL-23 (guselkumab, risankizumab, tildrakizumab) inhibitors. The objective of this narrative review is to revise efficacy and safety data of the latest biologicals, small oral molecules and biosimilar drugs for the treatment of chronic plaque psoriasis at Phase III of clinical development. The latest IL-17 and IL-23 inhibitors include bimekizumab, netakimab and mirikizumab as well as oral small molecules, such as deucravacitinib, a tyrosine kinase 2 selective inhibitor, and piclidenoson, an agonist of the Gi protein-associated A3 adenosine receptor. Additional molecules are in an early phase of development. Highly promising biologicals and small oral molecules are the leading edge of the systemic treatment of psoriasis.