There is something along the lines of roughly 15,000 sales tax jurisdictions in the US.
And while you might have had to collect and remit your sales taxes based on your box-store, you generally have the cushiness of having to keep up with 1 jurisdiction with 1 set of rules.
Now imagine having to collect and remit state sales tax for all 45 states.
Now imagine having to collect and remit sales taxes for individual jurisdictions (cities, counties, districts, water districts, metro transit authorities, parishes, etc.)
Now imagine having to collect and remit other related taxes and fees - e.g. If you buy a computer monitor in California you have to also charge a $2 disposal fee (In addition to the sales tax).
Now imagine having to comply with the laws and file returns for all of the above jurisdictions that you had a sale in.
Now imagine having to keep track of if your products/services is taxable or not in all 15,000+ jurisdictions e.g. groceries are exempt in my state, but certain items like sodas are not.
Now imagine having to keep track of many other different laws (e.g. Some states tax you based on the jurisdiction you deliver to [Ship-to address], some tax based on the origin [Ship-From] if it's an in-state sale.)
I'm probably going overboard describing all the issues/work involved for a small store doing small shipments - but I'm just trying to relay the message that it isn't easy