This brief review assesses the role of Ca2+ signaling in lung endothelium in regulation of endothelial permeability. The disconnect between experimental and clinical outcomes to date may be due, in part, to the use of tools which yield information about aggregate permeability or Ca2+responses in lung or in endothelial monolayers. The teaching point of this review is to “unpack the box,” i.e. consider the many potential issues which could impact interpretation of outcomes. These include phenotypic heterogeneity and resultant segment-specific permeability responses, methodologic issues related to permeability measures, contributions from Ca2+ channels in cells other than endothelium—such as alveolar macrophages or blood leukocytes), Ca2+ dynamic patterns, rather than averaged Ca2+ responses to channel activation, and the background context, such as changes in endothelial bioenergetics with sepsis. Any or all of these issues might color interpretation of permeability and Ca2+ signaling in lung.