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How do you get to your destinations and navigate yourself in the USA? Do you use gps systems such as google/apple maps?

I think like any other place, Google Maps is always going to be your friend. Downloading the offline version of maps can be really helpful for traveling around, especially in the subways of NYC!

Is it enough to simply follow road signs in the USA?

In short, yes, but the longer version is no because the size of the highways and interstates might be overwhelming to many (especially when driving on the other side of the road). Having a voice telling you which lane to be in at all times is safer and more efficient.

Is talking to locals and asking them directions the best way to get around? Are they generally friendly and helpful?

Speaking from NYC, absolutely it is. BUT (and it's a big one) do not try and get people's attention, or get in the way during peak commute hours (mornings between 8 and 10, and evenings between 5 and 7). You will get very different responses! Oh, and always keep right if you're walking. If you're going to stop, get right out of the way!

Are there any online resources or other types of resources to help you better understand the road systems, transportation, etc., in order to find your bearings?

Google Maps is plenty!

What are the steps to take if you get lost?

In NYC, remember that the Streets all run East/West and the Avenues all run North/South. Even streets go East as well. That will get you started, and then you can find your way much more easily.