San Luis Obispo sits almost exactly midway between Los Angeles (230 miles south) and San Francisco (230 miles north) on US-101. This makes it a natural stop on any coast drive, and the timing works out well: about four hours from either city, which is long enough that stopping feels warranted but short enough that you could realistically do it as a day trip from either end.
By car is the most common way to arrive. US-101 runs straight through town; downtown is a few minutes off the freeway. Highway 1 from the north is more scenic and adds time — it rejoins 101 near Morro Bay.
By train is genuinely convenient. The Amtrak Coast Starlight (Los Angeles–Seattle) stops in SLO, and the Pacific Surfliner runs daily from Los Angeles and San Diego. The station is a few blocks from downtown, and Amtrak provides connecting bus service to San Francisco. Train travel on this route is slow but scenic — the southern stretch along the Pacific between LA and SLO is among the better rail views in the country.
San Luis Obispo County Regional Airport (SBP) is a small airport with daily flights to Los Angeles, San Francisco, Phoenix, and Denver on United and American. It's not cheap, but the airport is five minutes from downtown and easier than driving from a distant major hub.
By bus, SLO Regional Transit operates local routes, and Greyhound and Flixbus serve the intercity routes along the 101 corridor.