INTRODUCTION: Psoriasis is a prevalent and widespread chronic immune disease and i s impacted by several variables. Although various medicines with diverse modes of operation have been licensed for the medical management of psoriasis, the ongoing investigation into its pathophysiological mechanisms, along with challenges related to administration and cost, has led to the increasing preference for new small molecule medications, namely janus kinase (JAK) and phosphodiesterase 4 (PDE4) inhibitors, in systemic therapy research. AREAS COVERED: This review takes a medicinal chemistry perspective to comprehensively explore the development as psoriasis therapy targets for small molecule inhibitors of JAK and PDE4. We describe the chemical space explored by medicinal chemists from 2010 to 2024, with particular emphasis on the importance of inhibitors with diverse scaffolds in studies of selectivity, potency and binding modes. EXPERT OPINION: Advancements in psoriasis treatment have shifted focus toward small-molecule drugs, such as JAK and PDE4 inhibitors, which offer advantages over biologics, including oral administration, improved cost-effectiveness, and reduced immunogenicity. Structural optimization based on receptor proteins and combination therapies further enhance drug performance and safety. Preclinical and clinical studies indicate that these strategies hold promise for developing more targeted, safer, and more effective treatments for psoriasis.