Syndromic conditions, such as sepsis, are commonly encountered in the intensive care unit. Although these conditions are easy for clinicians to grasp, these conditions may limit the performance of machine-learning algorithms. Individual hospital practice patterns may limit external generalizability. Data missingness is another barrier to optimal algorithm performance and various strategies exist to mitigate this. Recent advances in data science, such as transfer learning, conformal prediction, and continual learning, may improve generalizability of machine-learning algorithms in critically ill patients. Randomized trials with these approaches are indicated to demonstrate improvements in patient-centered outcomes at this point.