In terms of cost, from cheapest to most expensive:

1. Spot with autoscaling to adjust to demand and a savings plan that covers the ~75th percentile scale

2. On-demand with RIs (RIs will definitely die some day)

3. On-demand with savings-plans (More flexible but more expensive than RIs)

3. Spot

4. On-demand

I definitely recommend spot instances. If you're greenfielding a new service and you're not tied to AWS, some other providers have hilariously cheap spot markets - see http://spot.rackspace.com/. If you're using AWS, definitely auto-scaling spot with savings plans are the way to go. If you're using Kubernetes, the AWS Karpenter project (https://karpenter.sh/) has mechanisms for determining the cheapest spot price among a set of requirements.

Overall tho, in my experience, ec2 is always pretty far down the list of AWS costs. S3, RDS, Redshift, etc wind up being a bigger bill in almost all past-early-stage startups.

To "me, too" this, it's not like that AWS spot instance just go "poof," they do actually warn you (my recollection is 60s in advance of the TerminateInstance call), and so a resiliency plane on top of the workloads (such as the cited Kubernetes) can make that a decided "non-event". Shout out to the reverse uptime crew, a subset of Chaos Engineering