How you apply is determined by the type of job you're looking for:
Understand the Job Requirements
If you're applying for a specific job, get any information you can about the job, particularly the duties and qualifications. Tailor your resume, application information and particularly any cover letter you are able to send to reflect the job information, even using exact words and phrases from the job description. Too often people apply for jobs they are clearly not qualified for and then are disgruntled when they hear nothing or are rejected - don't waste time by applying for jobs on nothing but hope.
The other time waster is to apply to an employer when they aren't actively hiring. Sure it can be helpful to submit an application they can "keep on file" but don't get your hopes up. The best candidates are "fresh candidates". If it's been more than a few months since you submitted an application, do it again.
One step that could make the difference is to post your resume at an employer's online career site. They are more apt to search their resume database for keywords and those keywords might be in your resume.