Decades ago, surgeons hypothesized that esophageal bacteria played a key role in the emergence of infectious surgical complications, implementing studies however fail to report beneficial effects. Recent results on the role of the microbiota on outcomes in colorectal surgery have renewed interest in potential effect of the microbiome on surgical outcomes following esophageal surgery. Chapter 2 provides an overview of the available literature on the esophageal microbiome and its potential impact on outcomes following esophagectomy. Despite extensive research, the optimal surgical approach to an esophagectomy remains a topic of discussion. In chapter 3, the exact anatomical level of the esophagogastric anastomosis following an intrathoracic or cervical reconstruction was determined in distance from the incisors. Novel robot-assisted techniques used to create an intrathoracic anastomosis are summarized in chapter 4, helping to reduce learning curves when implementing robotic platforms. Finally, the question which surgical approach is preferred in patients at high-risk for postoperative complications is addressed in chapter 5. Propensity score matching was used to determine differences in short-term postoperative outcome following transthoracic or transhiatal surgery. Perioperative reinforcement of the esophagogastric anastomosis with tissue adhesives is a recent progression in attempt to reduce leakage rates. Tissue adhesives can be used as surgical sealants by enabling polymerization and forming tight approximation of the anastomosis. Chapter 6 reviews current literature on the use of tissue adhesives in esophageal surgery for prevention and treatment of anastomotic leakage. Chapter 7 describes a prospective cohort of esophagectomy patients and focused on the feasibility of additional sealing of the anastomosis by aerosolized spraying with autologous fibrin sealant. The detection of anastomotic leakage is challenging and current biochemical markers are known to lack specificity. This emphasizes the need to optimize current markers and development of novel, preferably non-invasive, biomarkers with high accuracy for predicting and diagnosing anastomotic leakage. Chapter 8 investigates the predictive value of routine C-reactive protein in a large prospective cohort to provide multiple new easy to use cut-offs for the assessment of major infectious complications. Furthermore, the diagnostic accuracy of urinary volatile organic compounds to detect anastomotic leakage has been investigated in chapter 9. A prospective cohort of colorectal patients was included in chapter 10 to examine the diagnostic accuracy of urinary volatile organic compounds in detecting anastomotic leakage after colorectal surgery. Chapter 11 describes a prospective diagnostic study to investigate whether urinary intestinal fatty acid binding protein could be useful as a non-invasive marker to detect colorectal anastomotic leakage. Finally, when findings are indicative for anastomotic leakage, CT imaging is justified as first diagnostic approach after esophagectomy. A novel systematic assessment of CT scans was proposed in chapter 12 by identifying reliable CT findings predicting anastomotic leakage and creating a practical scoring system to confirm or rule out this complication.