On quotes like this I point out "imagine the vastness of the universe. Now imagine that we are the only ones in it." Because according to all the scientific proof we now have, we are alone in the universe.
Which is why he was an "agnostic" when it came to extraterrestrial life. Our knowledge of the Universe is ever growing, and will continue to grow. Look at the Drake equation. Now, before anyone points it out, yes I know it is probability and I know that most of the entries at best are educated guesses. My point is look at the very first entries it requires. When the equation was first thought up, the margin of error was astronomical. Now, however many years later, we have a MUCH better grasp of our galaxy and our cluster. Whether it is theoretical and observable theories about various star systems, habitable zones, etc., we have come along way. At that time, we knew of no exo-solar planets that possessed the likelihood of any "earth-like" qualities, yet now we do. We truly are but a pale blue dot.
Yes, you can use quotations like "imagine the vastness of the universe. Now imagine that we are the only ones in it." or bring up Fermi to make us wonder, and question the principle of mediocrity, or jump of the rare earth hypothesis, but even then, in all of the matter, all of the dark matter, all of the energy, and all of the dark energy, we are still an insignificant speck in the Sol System, Local Spur, Milky Way, Local Group, Universe, etc...
One of the reasons I believe Dr. Sagan was and still is so popular was not only his attempts to make science "approachable", but also the marvellous language he used to describe it. We occupy and understand one n-tillionth of the Universe, we are insignificant. It is only anthropocentricism that tries to convince us otherwise. I believe the second point is metaphorical to emphasise how in the vastness of the Universe any one point is obscure. And the third question, I believe Dr. Sagan answers it himself later on the page, "We make our world significant by the courage of our questions and by the depth of our answers." His quotation is not supposed to be discouraging, rather humbling. As he said elsewhere "Lost somewhere between immensity and eternity is our tiny planetary home. In a cosmic perspective, most human concerns seem insignificant, even petty. And yet our species is young and curious and brave and shows much promise. In the last few millennia we have made the most astonishing and unexpected discoveries about the Cosmos and our place within it, explorations that are exhilarating to consider. They remind us that humans have evolved to wonder, that understanding is a joy, that knowledge is prerequisite to survival.
I believe our future depends on how well we know this Cosmos in which we float like a mote of dust in the morning sky." (Emph. mine). Without the pursuit of knowledge and endless questioning of our world and our Universe, we will render ourselves insignificant. We are a speck, we are a young speck, but we have potential if we allow growth.