While substantial progress has been made to improve the diagnosis, prognosis, and survivorship of patients with cancer, certain cancer types, along with metastatic and refractory disease, remain clinical challenges. To improve patient outcomes, ultimately, the cancer research community must meet and overcome these challenges, leading to improved approaches to treat the most difficult cancers. Here, we discuss research progress aimed at gaining a better understanding of the molecular and cellular changes in tumor cells and the surrounding stroma, presented at the 56th Irish Association for Cancer Research (IACR) Annual Conference. With a focus on poor prognosis cancers, such as esophageal and chemo-resistant colorectal cancers, we highlight how detailed molecular knowledge of tumor and stromal biology can provide windows of opportunity for biomarker discovery and therapeutic targets. Even with previously characterized targets, such as phosphoinositide 3-kinase (PI3K), one of the most altered proteins in all human cancers, new insights into how this protein may be more effectively inhibited through novel combination therapies is presented.