Human cytomegalovirus (HCMV) exhibits an exceptionally broad cellular tropism as it is capable of infecting most major organ systems and cell types. Definitive proof of an essential role for a cellular molecule that serves as an entry receptor has proven very challenging. It is widely hypothesized that receptor utilization, envelope glycoprotein requirements and entry pathways may all vary according to cell type, which is partially supported by the data. What has clearly emerged in recent years is that virus entry is not going undetected by the host. Robust and rapid induction of innate immune response is intimately associated with entry-related events. Here we review the state of knowledge on HCMV cellular entry mediators confronting the scientific challenges by accruing a definitive data set. We also review the roles of pattern recognition receptors such as Toll-like receptors in activation of specific innate immune response and discuss how entry events are tightly coordinated with innate immune initiation steps.