Despite the enormous progress made over the past decades in diagnosis, treatment and prevention of many types of tumor, the survival rate for pancreatic cancer still remains poor. Pancreatic cancer is one of the most malignant and chemotherapy-resistant tumors. That is mainly due to the lack of effective diagnosis at an early stage of tumor development and ineffective therapy. In most patients the disease is diagnosed at an advanced, metastatic stage and only 15-20% of patients are eligible for surgical removal of the tumor, which still remains the only chance for radical treatment. Studies in recent years have not yielded significant progress in the treatment of disease, and gemcitabine or its combinations with other chemotherapeutics such as erlotinib or capecitabine still remains the standard therapy. Although mechanisms of cell death induced by gemcitabine and other chemotherapeutic agents are well known, their effectiveness is limited due to the acquisition of drug resistance by pancreatic cancer cells. So far, mechanisms of resistance have been tested for mutations in many genes--the key to proper functioning of signaling pathways in cancer cells. However, recent studies suggest a significant role of the tumor microenvironment in the development and maintaining resistance to conventionally used chemotherapeutic and targeted therapies. Drug resistance of pancreatic cancer results from multiple mechanisms, which may include the following: mutations in key genes, aberrant gene expression, deregulation of key signaling pathways, apoptotic pathways, the capacity for epithelial-mesenchymal transition (EMT), increased angiogenesis, the presence of cancer stem cells or the presence of a hypoxic microenvironment inside the tumor.