Small molecule drugs have emerged as valuable therapeutic agents in the treatment of inflammation and cancer. However, there is still a need to identify additional molecular targets amenable to therapeutic exploitation. Pellino proteins form a three-membered family of E3 ubiquitin ligases, and an understanding of their crucial roles in regulating innate immunity and cancer is emerging. This understanding is largely gleaned from the use of experimental models, ranging from over-expression studies and gene knockdown/knockout approaches in cell models and the use of Pellino-deficient mice in disease models. Despite this, the potential to pharmacologically target Pellino proteins for therapeutic application in the treatment of inflammatory diseases or cancer remains largely unexplored. No candidate molecules have been described to date that effectively mimic or promote their function. However, recent work from my host laboratory has led to the design of two novel compounds intended to target Pellino proteins, especially Pellino2. This body of work aimed to investigate the regulatory effects of these novel compounds on the pathways and cells that drive inflammation, inflammatory diseases, and colorectal cancer. Initial studies identified that both compounds effectively inhibit inflammatory responses by targeting and facilitating the degradation of IRAK1. This led to the down-regulation of the NF-κB signaling pathway and the suppression of the expression of pro-inflammatory cytokines (e.g., IL-1β, IL-6, and TNFα) in a Pellino2-dependent manner. These effects were manifested at non�cytotoxic concentrations. Further studies supported a novel role for Pellino2 in protecting against pro-tumorigenic effects in colorectal cancer. The research revealed a down-regulation of human Pellino2 mRNA in colorectal cancer patients and cells, and a deletion of the Pellino2 gene in mice led to an increased tumor burden in preclinical models of colorectal cancer. The studies also demonstrated that human Pellino2 suppresses the growth and proliferation of colorectal cancer cells by promoting cell apoptosis. In promoting this pro-apoptotic effect, Pellino2 was shown to target the ubiquitination and degradation of Bcl-xL. Interestingly, while neither of the novel compounds designed to target Pellino2 consistently inhibited colorectal cancer cell growth, they did enhance the sensitivity of colorectal cancer cells to the cytotoxic effects of the chemotherapeutic agent Cisplatin in a Pellino2-dependent manner. Overall, this work reveals the promising potential of these novel compounds in targeting the pathways and cells that drive inflammatory diseases and colorectal cancer. It also highlights Pellino proteins as potential therapeutic targets in the development of innovative anti-inflammatory and anti-cancer therapeutics