I've used a number of solutions over the years. When I had my first kid I suddenly found that the back seat was no longer useful for cargo. (Especially because the wife insisted on a full complement of baby gear for a weekend trip.
I started by buying a locking box, mounting it to a board (that fit into my bed liner), and using a bike lock to lock that to the bed.
When she insisted that we had to take a high chair, some sort of scooty toy, and an activity center in addition to a month's worth of baby clothes (for a weekend--she wasn't sure what she'd want to dress the boy in), I ended up getting tonneau cover. As I already had a tool box, it was quite a search to find one that fit.
Six years and two more kids later, we are (she is) able to pack less stuff for three kids than we were (she was) ever able to for one.
And we bought a minivan.