The use of percutaneous mechanical circulatory support (pMCS), such as intra-aortic balloon pump, Impella, TandemHeart and VA-ECMO, in the setting of cardiogenic shock or in protect percutaneous coronary intervention (protect-PCI) is rapidly increasing in clinical practice. The major problem related to the use of pMCS is the management of all the device-related complications and of any vascular injury. MCS often requires large-bore access, if compared with common PCI, and for this reason the correct management of vascular access is a crucial point. The correct use of these devices in catheterization laboratories requires specific knowledge such as the correct evaluation of the vascular access performed, when possible, with advance imaging techniques in order to choose a percutaneous or a surgical approach. In addition to conventional transfemoral access, other types of access, such as transaxillary/subclavial access and the transcaval approach, have emerged over the years. These other approaches require advanced skills of the operators and a multidisciplinary team with dedicated physicians. Another important part of the management of vascular access is the closure systems used for hemostasis. Currently, two types of devices are typically used in the lab: suture-based or plug-based ones. In this review we want to describe all these aspects related to the management of vascular access in pMCS and describe, finally, a case report from our center’s experience.