With the assistance of wireless and Internet technologies, the Machine-to-Machine (M2M) devices are connected to the application servers to perform collaborative tasks and provide various applications with little or no human intervention. Based on a general network architecture summarized from the proposals of the 3rd Generation Partnership Project (3GPP), European Telecommunications Standards Institute (ETSI), and Telecommunications Industry Association (TIA), this paper discusses the network domain functionalities to accommodate trillions of M2M devices. Then we elaborate on issues such as significant signaling overhead that should be addressed so that the existing mobile networks can accommodate large-scale M2M communications. We analyze the overhead resulted from the M2M applications such as Intelligent Transportation System (ITS) and e-healthcare M2M applications. Our analysis is compared with those from the Human-to-Machine (H2M) and the Human-to-Human (H2H) applications.