Sarcoidosis is a multiorgan disease with no single etiology. Evidence over the years points to complex interactions between environmental and genetic factors and a hypersensitive immune response to these insults. This brief overview discusses the uncertainty in the diagnosis of sarcoidosis versus other granulomatous diseases masquerading as sarcoidosis. The diagnostic dilemma is highlighted by a brief case review. The development of newer techniques in molecular biology and the identification of a panel of biomarkers in the future with appreciable specificity and sensitivity would help in the process. Future studies to determine receiver operating curves (ROC) using multiple biomarker combinations would help develop robust testing. More in-depth studies are also needed for defining the immunological basis of sarcoidosis because recent studies implicate Th17 cells in addition to the Th1 cell pathway. It is very likely that direct exposure to environmental agents and systemic distribution of these agents can elicit an exaggerated immune response leading to multiorgan granuloma formation mimicking sarcoidosis. A genetically susceptible host may be necessary to complete the granulomatous response to the particulate matter.