Systems and methods for penetrating a tissue membrane to gain access to a target site are disclosed. In some examples, systems and methods for accessing the left atrium from the right atrium of a patient's heart are carried out by puncturing the intra-atrial septal wall. One embodiment provides a system for transseptal cardiac access that includes a guiding catheter, an access catheter and a guidewire. The access catheter may include a tissue penetration member disposed within a housing wherein the tissue penetration member is substantially contained within the housing when in a retracted configuration. When the distal end of the access catheter is disposed adjacent the septal wall, the user can initiate an actuator switch, which may be in a proximal portion of the system, to cause the tissue penetration member to extend through the septal wall. Alternatively, the tissue penetration member can be actuated automatically by a contact trigger mechanism, without initiation by the user, upon contact with the septal wall by a distal contact member which is coupled to the contact trigger mechanism. Such a system may also include an interlock mechanism to prevent triggering of the tissue penetration member at undesirable times during a procedure.