This is kind of a broad question, but something I've noticed is that in the pre-Renaissance era, many of the paintings in Europe tended to have featureless faces on the characters in the paintings. Some examples from this era:

1280: Triptych of Madonna and Child by Duccio

1333: The Annunciation by Martini

Then as the Renaissance progressed, faces began to approximate reality a bit more:

1482: Primavera by Botticelli

Early 1500s: Marriage of the Virgin by Raphael

Ultimately, the best artists got so good at painting faces that they were nearly life-like:

1540: Portrait of Doge Andrea Gritti by Titian

1634: Portrait of Haesje Jacobsdr. van Cleyburg by Rembrandt

So I understand that painters generally got better, but are there any specifics about changes in technique over this time? Why were old paintings of faces so uncanny compared to the later Renaissance? Did portraits like this one of Francis I of France in 1530 arouse that same uncanny sense at the time as it does today, or is it just that we're conditioned to see photorealism today that makes it so uncanny?