Most of the big publishers, and an increasing proportion of the smaller ones, state that they’ll no longer accept unsolicited manuscripts.
This doesn’t necessarily mean that you can’t submit to them: it just means that they have to solicit your manuscripts before they’ll even consider reading it.
One way to arrange this is to write a concise, appropriate and brilliant query letter. Tell them a little about your book: make them desperate to read it. If you can spark their interest sufficiently they’ll ask if they can read more and suddenly, your manuscript will be solicited.
Note that this won’t work with publishers who refuse unagented work: to be read by those publishers, you need to have an agent of your own. But it can open several doors that seem at first glance to be tightly locked shut.