Pancreatic cancer is one of the most lethal cancers worldwide, most notably in Europe and North America. Great strides have been made in combining the most effective conventional therapies to improve survival at least in the short and medium term. The start of treatment can only be made once a diagnosis is made, which at this point, the tumor volume is already very high in the primary cancer and systemically. If caught at the earliest opportunity (in circa 20% patients) surgical resection of the primary followed by combination chemotherapy can achieve 5-year overall survival rates of 30%–50%. A delay in detection of even a few months after symptom onset will result in the tumor having only borderline resectabilty (in 20%–30% of patients), in which case the best survival is achieved by using short-course chemotherapy before tumor resection as well as adjuvant chemotherapy. Once metastases become visible (in 40%–60% of patients), cure is not possible, palliative cytotoxics only being able to prolong life by few months. Even in apparently successful therapy in resected and borderline resectable patients, the recurrence rate is very high. Considerable efforts to understand the nature of pancreatic cancer through large-scale genomics, transcriptomics, and digital profiling, combined with functional preclinical models, using genetically engineered mouse models and patient derived organoids, have identified the critical role of the tumor microenvironment in determining the nature of chemo- and immuno-resistance. This functional understanding has powered fresh and exciting approaches for the treatment of this cancer. Graphical Abstract The current and emerging status of pancreatic cancer therapy. The left-hand panel shows a schematic representation of the estimated response rates to therapies based on tumor cell mass (the primary tumor and metastasis combined) and time assuming Gomp-Ex tumor cell growth rates. (A mathematical sigmoid function which describes growth as being slowest at the start and end of a given time period was proposed by Benjamin Gompertz in 1825 [Philosophical Transactions of the Royal Society of London]. This was modified for tumor cell growth by TE Wheldon in 1988 [Mathematical Models in Cancer Research], in which the cellular population expands exponentially [Gomp-Ex] on the assumption that initially there is no competition for resources. More complex models are needed to describe metastatic seeding and growth.) The start of treatment can only be made once a diagnosis is made, which at this point the tumor volume is already high in the primary cancer and in micrometastases around the body. If caught at the earliest opportunity (in circa 20% patients) surgical resection of the primary followed by combination chemotherapy can achieve 5-year overall survival rates of 30%–50%. A delay in detection of even a few months after symptom onset will result in the tumor having only borderline resectabilty (in 20%–30% of patients), in which case the best survival is achieved by using short-course chemotherapy before tumor resection as well as adjuvant chemotherapy. Once metastases become visible (in 40%–60% of patients), cure is not possible, palliative cytotoxics only being able to prolong life by a few months. The right-hand panel demonstrates the multiple approaches being undertaken to deepen the understanding of the nature of pancreatic cancer and its responses to different therapies. There is much to be gained from functional preclinical models (genetically engineered mouse models and patient-derived organoids), but the emphasis has shifted to deeper investigations of patient tumors within the context of clever multidisciplinary prospective clinical studies. [ABSTRACT FROM AUTHOR]