Prague has highway connections from all around. Highways, expressways (very similar to highways and having the same speed limit) and first-class roads in the Czech Republic meet European standards and are well marked, with many gas stations alongside. Other roads are usually uneven and poorly marked.
When travelling on highways and expressways, you must have a vignette (except for small in-town sections which are extempt and marked so). You can buy 10-day, monthly, or annual vignettes at gas stations, post offices, or border crossings CZ government motorway site. You should write your license plate number on it and place it on your windshield from the inside, in the lower right-hand corner. Failure to display the vignette is fined on the spot. The vignette has a second part which you fill in with your license plate number as well and save it for any future police check-up. If your car weighs over 3.5 tons, you need a toll unit (“premid”) instead, which is required on first-class roads as well (marked with M in a circle).
The southeastern highway (D1, E50 and E65) is the Czech Republic's oldest and most used highway but it's undergoing a massive reconstruction so expect delays and diversions. It leads through Brno to Bratislava in Slovakia. It offers a good connection to Vienna, Budapest and all traffic from the east. It runs for about 270 km (165 mi) and usually takes about two hours to Brno.
The southern highway (D3, E55) is not completed up to Prague, part of D1 and then first-class road 3 are used instead; traffic is very heavy on this road. There is also a southern expressway R4 but it goes on the other side of Vltava and is in quite a bad shape.
The southwestern highway (D5, E50) leads through Plzeň to Germany where it continues as A6. Riding from the state border to Prague takes about an hour and a half (151 km / 94 mi).
To the west, there is expressway R6 (E48) leading to Karlovy Vary and Cheb. Only about one fourth is completed with heavy traffic in the other sections.
The northwestern expressway R7 leads to Chomutov and Chemnitz. Near Prague, only very small part is finished. Václav Havel Airport is located on this expressway.
To the north, you can take highway D8 (E55), but it is not complete to the German border. It ends now at Lovosice (about 60 km / 37 mi from Prague) and starts again in Ústí nad Labem and continues to the northern Germany via A17 (Dresden, Berlin, Leipzig).
To the northeast, you can take expressway R10 (E65). It leads to Liberec and Turnov. It is not regarded as an important access route as there are no major cities in this direction (Zittau in Germany, some cities in Poland) but it offers a good connection to the Czech mountains Jizerské hory and Krkonoše (Riesengebirge) with the best Czech skiing resorts.
To the east, you can take the newly completed D11 (E67) which goes to Hradec Kralove and Poland.
About half of the city is encompassed with the ring expressway R1 while the other half is still waiting to be completed. During work days, prefer to use this road instead of going through the jammed city as many GPS suggests.
Lot of Czech highways are unfinished and are under development (D8 and D11 being extended, D3 to České Budějovice and Linz was supposed to be completed in 2020 but has been delayed and no new date has been set) so things will get better. Unless there are road works, there are only seldom traffic jams on Czech highways with the exception of D1 between Prague and Mirošovice (where first-class road 3 splits).
Prague suffers from heavy traffic and on week days the main streets are one big traffic jam. It is a really good idea to use the P+R (park and ride) parking places where you can park your car for a very small fee and use public transport (however these are usually full on week days as well).
The P+Rs are situated near all highways and are well marked. Note that traffic wardens are rife and parking in most residential streets in and around Prague city center without a valid permit will result in a parking fine. In particular, avoid blue-marked areas which are residents-only (all time) and cars are regularly towed away. Orange and green-marked areas are designed for 2-hour and 6-hour paid parking but spots are usually hard to find; parking in these areas is mostly unlimited and free on weekends and during night but check the signs. There is a reasonable number of other paid parking options in the city center though, such as Václavské Gáráže, Mr. Parkit, or Vincipark.